PI3K/AKT signaling pathway: molecular crossroads in tumorigenesis and therapeutic innovation

Abstract

The PI3K/AKT signaling pathway serves as a pivotal regulatory hub that governs essential cellular processes, including growth, proliferation, metabolism, survival, and migration. In the context of tumorigenesis and cancer development, aberrant activation of this pathway drives malignant transformation, enhances invasive and metastatic potential, and confers resistance to therapeutic interventions, ultimately resulting in tumor progression and poorer clinical outcomes. This study comprehensively investigates PI3K/AKT signaling, elucidating its involvement across diverse human systemic tumors and analyzing the interplay between this pathway and other signaling cascades implicated in tumorigenesis. Emphasis is placed on mechanistic insights into the role of the PI3K/AKT pathway in tumor initiation and progression across various systems, alongside an overview of therapeutic strategies targeting PI3K/AKT signaling. Notably, advances in research on the PI3K/AKT pathway have identified a wide array of potential therapeutic targets, facilitating significant progress in related treatment modalities. Given the extensive involvement of PI3K/AKT signaling in diverse biological processes, optimizing the therapeutic efficacy of PI3K/AKT-targeted interventions while minimizing associated adverse effects remains a critical challenge, necessitating innovative approaches for substantial therapeutic breakthroughs. Therefore, a systematic and nuanced understanding of the pathway’s role in tumor biology is essential for advancing foundational research and informing future clinical developments in this field.

Introduction

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway constitutes a complex regulatory network encompassing the PI3K family, AKT, and downstream effector molecules.¹ PI3K, a lipid kinase, modulates intracellular vesicle transport and various cell signaling pathways, while AKT, a serine/threonine-specific protein kinase, is integral to cell survival and apoptosis regulation.^2,3 Activation of the PI3K/AKT signaling pathway is essential for promoting cell survival and proliferation.⁴ Additionally, this conserved transduction network is ubiquitous among higher eukaryotic cells, serving as a fundamental component of cellular signaling processes.⁵ The PI3K/AKT cascade facilitates dynamic interactions between growth factors and transcription factors, functioning within a highly regulated framework that interconnects with diverse cellular signaling networks.⁶ Oncogenes and growth factor receptors activate PI3K enzymes, a mechanism widely recognized as a critical driver of tumor transformation.⁴ Consequently, dysregulation of the PI3K/AKT pathway significantly impacts key oncogenic processes, including autophagy, epithelial–mesenchymal transition (EMT), metabolic reprogramming, drug resistance, angiogenesis, and immune evasion.^7,8

Aberrant PI3K/AKT signaling is a major contributor to tumor initiation and progression, with abnormal activation detected in various carcinomas, including those of the head, neck, lung, pancreas, breast, and prostate.^9–11 Given the pivotal role of this pathway in tumor progression, extensive research has focused on developing inhibitory agents, such as dual PI3K-mammalian target of rapamycin (mTOR) inhibitors, AKT inhibitors, PI3K inhibitors, and mTOR catalytic site inhibitors.^12,13 These therapeutic agents not only inhibit tumor cell growth and survival signals but also impact angiogenesis and energy metabolism.¹⁴ Numerous inhibitors targeting the PI3K/AKT signaling cascade have shown clinical efficacy, and additional compounds are currently under investigation.^15,16

This review critically examines the biological foundation of the PI3K/AKT pathway, including its self-regulatory mechanisms and interactions with other signaling cascades. It provides a comprehensive synthesis of recent progress in elucidating the pathway’s role in tumor pathogenesis across diverse systems and discusses novel therapeutic approaches. This analysis offers an updated perspective on PI3K/AKT signaling in oncology, contributing valuable insights to advance both research and clinical applications.

Composition of the PI3K/AKT pathway

The PI3K/AKT signaling cascade plays a central role in regulating key cellular biological processes, such as cell survival, apoptosis, and metabolic activities, primarily mediated through PI3K activation and subsequent AKT phosphorylation.^17,18 Mutations affecting specific components of the PI3K/AKT pathway can induce cellular transformation, influence the proliferation and viability of tumor cells and are closely linked to tumor invasion and metastasis.¹⁹

The PI3K family

The PI3K/AKT pathway plays a critical role in regulating various physiological functions, including cell proliferation, migration, and metabolic control. However, hyperactivation of this pathway in diverse human tumors has been associated with tumor initiation, resistance to anticancer therapies, and poor clinical outcomes.^20,21

Class I PI3K

Class I PI3K, the most extensively studied subtype, exhibits a robust association with tumorigenesis.²² Class I PI3Ks are capable of catalyzing the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP₂) at the 3-OH position of the inositol ring on the cell membrane, leading to the generation of phosphatidylinositol 3,4,5-trisphosphate (PIP₃).²³ This enzymatic reaction is mediated by the catalytic subunits of PI3Ks, which utilize ATP as a phosphate donor and are regulated by upstream signaling activation.³ It comprises four catalytic isoforms: p110α, p110β, p110γ, and p110δ, encoded by the genes PIK3CA, PIK3CB, PIK3CG, and PIK3CD, respectively.²² Among these isoforms, p110α frequently harbors oncogenic mutations, making it a prominent driver in human tumors.²⁴ In contrast, p110β, p110δ, and p110γ mutations are rare, although overexpression of these isoforms has been observed in certain cancer types. Additionally, mutations or loss of expression of the p85α regulatory isoform are linked to tumor development.²⁵

Mutations in PIK3CA are prevalent across a wide range of human malignancies, predominantly occurring at residues H1047, E542, and E545 within the catalytic subunits of class I PI3K. In contrast, mutations in the remaining catalytic subunits (β, δ, and γ) are significantly less common, with PIK3CB mutations being particularly rare.^26,27 Notably, PIK3CG has been recognized as a critical mediator driving immunosuppressive programming within tumor-associated macrophages.²⁸

In mammals, Class I PI3Ks are categorized into two subclasses—IA and IB—distinguished by their regulatory mechanisms.²⁹ Subclass IA PI3Ks consist of three catalytic proteins: p110α, p110β, and p110δ.³⁰ These catalytic subunits form heterodimers with the regulatory subunit p85, creating a functional complex.³¹ In contrast, class IB PI3Ks consist of the catalytic subunit p110γ that associates with regulatory isoforms p101 or p87.³² Based on their catalytic subunits, these PI3K variants are designated PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ, respectively.³³ PI3Kα and PI3Kβ exhibit broad expression across multiple cell types, whereas PI3Kδ and PI3Kγ are predominantly expressed within the immune system.^34–36 Dysregulation of PI3Kα is frequently associated with tumor resistance to therapy, positioning PI3Kα as a primary target in anticancer drug development.³⁷ In cancer individuals with a deletion of the phosphatase and tensin homolog (PTEN) gene, PI3Kβ plays a pivotal role.³⁸ Inactivation of PI3Kβ in a PTEN-deficient context has been shown to reduce STAT3 signaling and enhance the expression of immune stimulatory molecules, thereby promoting antitumor immune responses. PI3Kδ serves as a critical signal transduction hub within immune cells,^39,40 while the PI3Kγ enzyme is integral to both cardiovascular and immune functions. The p110γ isoform, in particular, facilitates the migration of immune cells toward inflammatory sites.^41,42 Activation mechanisms also differ between the subclasses. Class IA PI3Ks are activated upon binding of the regulatory subunit’s SH2 domain to phosphotyrosine residues on activating receptors, including receptor tyrosine kinases (RTKs), or adapter proteins.⁴³ In contrast, class IB PI3Ks are primarily activated through interactions with G-protein-coupled receptors (GPCRs).⁴⁴

Class II PI3K

Class II PI3Ks can phosphorylate phosphatidylinositol (PI) and phosphatidylinositol 4-phosphate (PIP) to produce phosphatidylinositol 3-phosphate (PI3P) and PI(3,4)P2, respectively.⁴⁵ While class I PI3Ks produce PIP₃, class III PI3Ks generate PI3P in living organisms.^46,47 The first class II PI3K gene identified was Pi3K68D in Drosophila, which is homologous to piki-1 in Caenorhabditis elegans.⁴⁸ In mammals, the three isoforms of class II PI3K—PI3KC2α, PI3KC2β, and PI3KC2γ—are encoded by the genes PIK3C2A, PIK3C2B, and PIK3C2G, respectively. These monomeric lipid kinases lack regulatory subunits.⁴⁹

PI3KC2α and PI3KC2β exhibit widespread expression patterns, while PI3KC2γ shows predominant expression in hepatic tissues.⁵⁰ PI3KC2β is pivotal in endothelial signaling and modulates vascular growth by inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling within endothelial cells.⁵¹ The loss of PI3KC2γ in pancreatic ductal adenocarcinoma (PDAC) increases the sensitivity of cancer cells to combined mTORC1 and glutaminase inhibition, promoting accelerated tumor progression.⁵² Although the precise functional mechanisms of class II PI3Ks remain incompletely characterized, both PIK3C2A and PIK3C2B have been implicated in critical physiological functions and tumorigenesis.⁵³ As a representative member of the class II PI3K family, PIK3C2A has been linked to cancer-related pathways, primarily due to its lipid phosphorylation activity.^54,55 Amplification of PIK3C2B has been reported in glioblastoma (GBM), highlighting its potential oncogenic role.⁵⁵ Moreover, PIK3C2G is vital in regulating cellular metabolism, and its deficiency significantly affects glycogen synthase activation.⁵⁶

AKT

AKT, commonly referred to as protein kinase B, was originally discovered in the 1970s as an oncogene transduced by a transforming retrovirus (AKT-8) derived from an AKR mouse thymoma cell line.⁵⁷ AKT participates in numerous biological functions, including cell growth, survival, glucose homeostasis, protein synthesis, genomic stability, and inhibition of apoptosis in response to growth factors and external signals.⁵⁸ Humans possess three AKT isoforms, AKT1, AKT2, and AKT3, which share structural similarity and activation mechanisms but exhibit distinct tissue distribution and functional roles.⁵⁷ AKT1 and AKT2 are ubiquitously expressed, with AKT2 playing a critical role in insulin-responsive metabolic tissues, while AKT3 demonstrates a restricted expression pattern, primarily in the brain.⁵⁹ Functional studies have revealed contrasting roles of AKT1 and AKT2 in cell migration and invasion.⁶⁰ In breast cancer (BC), AKT1 inhibits tumor cell migration and proliferation, whereas AKT2 enhances these processes.^61,62 In prostate cancer (PCa), AKT1 activation through integrin signaling promotes cell motility, invasion, and trans-endothelial migration.⁶³ In GBM, silencing AKT3 expression significantly impedes the growth of spheroids and xenografts.⁶⁴

AKT, a downstream effector of PI3K, contains two essential phosphorylation sites, Thr308 and Ser473, corresponding to its kinase and regulatory domains, respectively.^65,66 PIP3, an active lipid molecule positioned upstream within the PI3K/AKT/mTOR signaling pathway, acts as a secondary messenger by promoting the translocation of phosphoinositide-dependent kinase-1 (PDK1) and AKT to the plasma membrane upon its generation.⁶⁷ PDK1 subsequently phosphorylates Thr308, partially activating AKT.⁶⁸ Studies have identified that mTORC2 specifically phosphorylates Ser473, thereby enhancing AKT activity.^69,70 Glycogen synthase kinase 3 (GSK3) was the first identified AKT substrate, executing inhibitory control by phosphorylating downstream targets.⁷¹ AKT modulates apoptosis and cell survival via phosphorylation-induced inhibition of specific B-cell lymphoma 2 (Bcl-2) family members.⁷² Inhibition of Bcl-2 has been reported to trigger autophagy-mediated cell death in BC cells overexpressing Bcl-2.⁷³ Concurrently, AKT facilitates NF-κB activation by phosphorylating and inhibiting IκB kinase, thereby modulating inflammation and promoting cell survival.⁷⁴ The forkhead box O (FOXO) protein family, a prominent substrate within the AKT pathway, undergoes cytoplasmic sequestration upon phosphorylation, suppressing the transcription of its target genes.^75,76 Inhibition of FOXO by AKT has been correlated with various tumorigenic processes, including initiation and progression.^77,78 Due to its aberrant activation, AKT significantly contributes to the pathogenesis of complex diseases and has emerged as a strategic therapeutic target in oncology, prompting the development of numerous AKT-targeting pharmaceutical compounds.^79,80

PTEN

PTEN represents one of the most crucial tumor suppressor gene products and serves as a key negative regulator upstream of the PI3K/AKT/mTOR pathway.⁸¹ Localized on chromosome 10q23, the PTEN gene consists of nine exons that encode a 403-amino-acid protein with an approximate molecular weight of 48 kDa.⁸² Functionally, PTEN acts as a lipid phosphatase that directly counteracts PI3K activity by promoting the conversion of PIP3 to PIP2 through dephosphorylation.⁸³ This enzymatic action prevents the accumulation of PIP3 at the plasma membrane, thereby blocking the recruitment and subsequent activation of AKT and its downstream effectors. Through this regulatory mechanism, PTEN plays a critical role in preserving cellular homeostasis by modulating essential biological functions, including cell proliferation, survival, metabolism, migration, and genomic stability.⁸⁴ Moreover, accumulating evidence suggests that PTEN also regulates various immune signaling molecules and T-cell developmental regulators, highlighting its emerging role in immune modulation.⁸⁵ As a central “gatekeeper” of the pathway, loss or functional inactivation of PTEN—frequently observed in multiple cancers through mechanisms including mutations, deletions, or epigenetic silencing—results in unchecked activation of the PI3K/AKT signaling cascade.⁸⁶ Consequently, constitutive hyperactivation of this pathway promotes malignant behaviors such as uncontrolled cell growth, resistance to apoptosis, altered metabolism, and metastatic potential in cancers such as glioblastoma, prostate cancer, BC, endometrial carcinoma, and melanoma.^87,88 Additionally, PTEN haploinsufficiency has been implicated in tumor-predisposition syndromes such as Cowden syndrome.⁸⁹ Beyond its canonical lipid phosphatase activity, PTEN localized in the cytoplasm or nucleus exerts PI3K-independent tumor-suppressive functions, including the regulation of DNA repair and chromosomal integrity, further emphasizing its multifunctional significance in both physiological and pathological contexts.⁹⁰

mTOR

mTOR complexes, mTORC1 and mTORC2, function as key downstream effectors and central integration nodes within the PI3K/AKT pathway. mTORC1 is the primary mediator responsible for regulating essential cellular functions such as cell growth, proliferation, and metabolic activity.⁹¹ mTORC2 phosphorylates AKT at Ser473, amplifying AKT signaling through a positive feedback mechanism and functioning upstream/downstream of AKT.⁹²

Pathological hyperactivation of mTORC signaling, commonly driven by activating mutations in the upstream PI3K/AKT pathway or direct genetic alterations in mTOR pathway components (e.g., loss of TSC1/2 or mutations in mTOR), is a hallmark of multiple cancers and other pathological conditions.⁵ Specifically, aberrant mTORC1 activation promotes uncontrolled cell growth and proliferation through enhanced biosynthesis of proteins, lipids, and nucleotides, suppression of autophagy, and stimulation of angiogenesis. Furthermore, mTORC2 dysregulation enhances tumor cell survival, migration, invasion, and metastasis via AKT-dependent mechanisms and cytoskeletal remodeling.⁹³ Collectively, this disrupted mTOR signaling contributes to oncogenesis, metabolic reprogramming, and resistance to therapy. Consequently, rapalogs such as everolimus and temsirolimus, which selectively inhibit mTORC1, have been approved for the treatment of various malignancies, including renal cell carcinoma, BC, and neuroendocrine tumors.^94,95 Additionally, next-generation ATP-competitive mTOR inhibitors are currently under clinical development.⁹⁶

Crosstalk of the PI3K/AKT pathway with other signaling cascades

A signaling pathway encompasses a series of enzymatic reactions through which extracellular signaling molecules are transduced across the cell membrane, eliciting intracellular effects. Classical signaling cascades, including the NF-κB, mitogen-activated protein kinase (MAPK), Janus kinase/signal transducer and activator of transcription (JAK/STAT), transforming growth factor β (TGF-β), Wnt, Notch, and Hedgehog pathways, have been extensively investigated in biological research.⁹⁷ These pathways have demonstrated potential interactions with the PI3K/AKT cascade, playing pivotal roles in diverse biological processes (Table 1). Elucidating the crosstalk between these pathways will deepen the understanding of the PI3K/AKT signaling cascade (Fig. 1).

Table 1.

Crosstalk of PI3K/AKT pathway

Associated signaling pathway	Associated diseases	Related genes	Mechanism	Ref.
Wnt signaling pathway	Prostate cancer	FOXO3a, β-catenin	FOXO3a inhibits β-catenin transcriptional activity and regulates EMT-related markers	110
	Colorectal cancer	AKT, GSK3β	Activate the PI3K/AKT pathway, suppress GSK-3β phosphorylation	111
	Triple-negative breast cancer	PI3Kα, Wnt/β-catenin	Promote the formation and transport of PI3Kα and activates the Wnt/β-catenin signaling pathway	113
NF-κB signaling pathway	Autoimmune hepatitis	AKT, Ikα, IκB, NF-κBp65	Increase the phosphorylation levels of IKα, IκB, and NF-κB p65 subunits	124
	Hepatocellular carcinoma	PI3K, AKT, NF-κBp65	Promoting aerobic glycolysis through the NF-κBp65/HK2 pathway leads to excess lactate production and activates the PI3K/AKT signaling pathway	125
MAPK/ERK pathway	Melanoma	P-AKT, P-ERK	PIK3CA inhibitor elevate the level of p-ERK	136
	Glioblastoma multiforme	KRAS, PTEN	Activate KRAS and/or delete PTEN	138
JAK/STAT signaling pathway	Diseases related to the mammary gland	p58α, JAK2, STAT5	Regulate the p58α regulatory subunit of PI3K	148
	Myocardial infarction	PTEN	Inhibit apoptosis through the PTEN signaling pathway	149
TGF-β signaling	Breast cancer	AKT, TGF-β2	Activate AKT, phosphorylates Twist1, increase secretion of TGF-β2	161
Notch signaling pathway	Glioblastoma	Notch1	Suppress the Notch1 pathway, inhibit the PI3K/AKT pathway	169
Hedgehog signaling	Acute myeloid leukemia	PI3K, AKT, GSK3	Regulate the cell cycle	180

Fig. 1.

Crosstalk of the PI3K/AKT signaling pathway. The PI3K/AKT signaling pathway exhibits extensive interactions with classical signaling cascades, including the NF-κB, MAPK, JAK/STAT, TGF-β, Wnt, Notch, and Hedgehog pathways, playing pivotal roles in a wide array of biological processes. NADPH nicotinamide adenine dinucleotide phosphate, PTEN phosphatase and tensin homolog, PI3K phosphatidylinositol 3-kinase, AKT protein kinase B, EMT epithelial–mesenchymal transition, INPP4B inositol polyphosphate 4-phosphatase type II, HK2 hexokinase 2, STAT signal transducer and activator of transcription, TGF-β transforming growth factor beta, GSK3 glycogen synthase kinase 3. Figure created with BioRender (https://www.biorender.com)

Crosstalk of PI3K/AKT signaling with Wnt signaling

The Wnt pathway is fundamental for regulating normal tissue development and comprises two primary types: β-catenin-dependent (canonical) and β-catenin-independent (noncanonical) pathways.⁹⁸ The canonical Wnt pathway regulates cellular biological processes, while the noncanonical Wnt pathway predominantly governs cell polarity and motility.^99,100 In the canonical pathway, binding of Wnt ligands to their receptors promotes the nuclear translocation of β-catenin.¹⁰¹ In the absence of Wnt binding, β-catenin is marked for proteasomal degradation by a destruction complex, which is typically inhibited upon Wnt activation.¹⁰² Conversely, the noncanonical Wnt pathway, independent of β-catenin, involves various Wnt5a ligands.¹⁰³ Reactive oxygen species (ROS) generation stimulates the PI3K/AKT pathway, whereas PTEN acts as a negative regulator.¹⁰⁴ PTEN undergoes oxidative inactivation through NADPH oxidase and superoxide dismutase, resulting in impaired PTEN function,¹⁰⁵ thereby enhancing AKT activity. This activation leads to GSK3β phosphorylation by AKT, preventing inhibition of nuclear β-catenin signaling and facilitating tumor cell proliferation.^106,107 FOXOs, a subfamily of forkhead box transcription factors, represent key downstream targets within the AKT pathway.¹⁰⁸ AKT-mediated phosphorylation of FOXOs regulates cell viability.¹⁰⁹ In PCa cells, FOXO3a has been identified as an inhibitor of β-catenin transcriptional activity, modulating EMT markers and suppressing EMT progression in prostate adenocarcinoma.¹¹⁰ In colorectal cancer (CRC), PI3K activation triggers AKT phosphorylation, subsequently promoting GSK3β phosphorylation at Ser9, which suppresses GSK3β kinase activity and modulates EMT in CRC cells.^71,111 INPP4B, a known tumor suppressor in triple-negative BC, has been observed to facilitate the proliferation of ER-positive BCs with PIK3CA mutations.¹¹² This effect is mediated through PI3Kα-dependent late endosome formation and trafficking, subsequently activating the Wnt/β-catenin cascade.^113,114

Crosstalk of PI3K/AKT signaling with NF-κB signaling

The NF-κB pathway encompasses canonical and noncanonical signaling branches.¹¹⁵ The mammalian NF-κB transcription factor family consists of five members, all of which contain a conserved Rel homology domain that facilitates the formation of homo or heterodimers between family members.^116,117 These dimers interact with IκB and are retained in the cytoplasm in an inactive form, where the p65/p50 heterodimer represents the most common configuration.¹¹⁸ Canonical NF-κB signaling is primarily triggered by stimuli, including TNF-α, interleukin (IL)-1β, lipopolysaccharide, and antigens.¹¹⁹ Rapid activation of canonical NF-κB occurs in both innate and adaptive immune cells via various signals transmitted through pattern-recognition receptors, T-cell receptors, B-cell receptors, proinflammatory cytokine receptors, and related pathways.^119,120 The I-kappaB kinase (IKK) complex, a pivotal component of NF-κB signaling, comprises three subunits: IKKα, IKKβ, and NEMO (also known as IKKγ).¹²¹ Among these, IKKα and IKKβ function as catalytic kinases, while IKKγ serves as a regulatory element.¹²² CCN1, an extracellular matrix-associated protein with heparin-binding properties, is associated with the development and progression of multiple diseases.¹²³ Activation of the PI3K/AKT signaling pathway is significantly enhanced following CCN1 treatment, as evidenced by increased phosphorylation of AKT.¹²⁴ In autoimmune hepatitis, CCN1 markedly elevates the phosphorylation levels of IκB, IKKα, and the NF-κB p65 subunits, promoting nuclear translocation of NF-κB p65 and subsequently initiating gene transcription.¹²⁴ In hepatocellular carcinoma (HCC), the hepatitis B virus X protein (HBx) has been found to promote aerobic glycolysis via the NF-κB p65/hexokinase 2 (HK2) axis, leading to increased lactate production. This metabolic shift subsequently activates the PI3K/AKT signaling pathway, fostering pathological hepatocyte proliferation and contributing to HBx-induced hepatocarcinogenesis.¹²⁵

Crosstalk of PI3K/AKT signaling with the MAPK/ERK pathway

The MAPK family, a member of the serine-threonine kinase group, is pivotal in regulating a wide array of cellular processes.¹²⁶ The MAPK family is categorized into three primary subfamilies: extracellular-signal-regulated kinases (ERK), c-jun N-terminal kinase or stress-activated protein kinases (JNK or SAPK), and MAPK14.^127,128 Based on the signal transduction mechanism, the MAPK signaling pathway can be subdivided into the conventional and atypical MAPK signaling pathways.¹²⁹ The conventional MAPK pathway involves signal transmission through the sequential activation of MAPKKK, MAPKK, and MAPK. In contrast, atypical MAPK signaling pathways, regulated by ERK3/ERK4, ERK7/ERK8, and Nemo-like kinase cascades, deviate from this classical activation pattern.^130,131 The MAPK/ERK pathway encompasses a series of protein kinases, including RAS, RAF, MEK, and ERK.¹³² RAS proteins, functioning as GTP-binding molecules, are integral to cellular signaling.¹³³ Upon activation, RAS directly interacts with and activates RAF, which subsequently initiates the MAPK/ERK signaling cascade.¹³⁴ The p110 catalytic subunit of class I PI3K, containing RAS-binding domains, facilitates the recruitment of the p110 catalytic subunit to the plasma membrane upon RAS activation, thereby triggering the AKT pathway.¹³⁵ In melanoma cells, treatment with the PIK3CA inhibitor (BYL719) alone resulted in increased p-ERK levels across all transduced cells, suggesting an interaction between the MAPK and PI3K/AKT pathways. This observation indicates that suppressing p-AKT may trigger a compensatory upregulation of p-ERK, reflecting an adaptive response to the disruption of the PI3K/AKT signaling.¹³⁶ KRAS, a commonly mutated proto-oncogene in tumors, belongs to the RAS superfamily.¹³⁷ PTEN, a tumor suppressor and negative regulator of the PI3K pathway, plays a critical role in modulating cell proliferation and migration.¹³⁸ In GBM, KRAS activation and/or PTEN deletion not only enhance MAPK and PI3K signaling pathways but also promote the growth and migration of astrocytes with G1/S checkpoint defects.¹³⁹ In gastric cancer (GC), solute carrier family 39 member 10 (SLC39A10) forms a feedback loop with c-Myc, contributing to tumorigenesis by facilitating zinc ion efflux, which in turn activates the MAPK/ERK and PI3K/AKT signaling pathways through casein kinase 2-mediated mechanisms.¹⁴⁰ The intricate crosstalk between the PI3K/AKT and MAPK/ERK pathways highlights the intricate nature of the oncogenic signaling network. A comprehensive understanding of the dynamic interactions among these signaling pathways is crucial for developing effective therapeutic strategies to overcome drug resistance in cancers driven by such interconnected mechanisms.

Crosstalk of PI3K/AKT signaling with the JAK/STAT pathway

The JAK/STAT pathway, a highly conserved signaling axis, is essential for immune cell function, lipid metabolism, thrombosis, and numerous biological processes.¹⁴¹ This pathway comprises receptor‒ligand complexes, JAKs, STAT proteins, and the SOCS/CIS protein family, which contains Src homology 2 (SH2) domains.^142,143 Four JAK isoforms (JAK1, JAK2, JAK3, and TYK2) undergo phosphorylation to activate downstream STATs.¹⁴⁴ JAK proteins are characterized by distinct domains, including FERM (four point one, ezrin, radixin, and moesin complex), SH2, pseudokinase, and kinase domains.¹⁴⁵ The STAT family, comprising seven members (STAT1-4, STAT5A, STAT5B, and STAT6), is involved in regulating survival, differentiation, metabolism, and immune responses.¹⁴⁶ AKT decreases the binding and inhibitory effect of salt-inducible kinase 1 on STAT3 through a phosphorylation-dependent mechanism, thereby promoting tumorigenesis in breast cells.¹⁴⁷ These findings indicate that STAT3 may represent a promising therapeutic target in BC subtypes with elevated AKT activity. In mammary epithelial cells, the JAK2/STAT5 pathway directly interacts with the p58α regulatory subunit of PI3K to regulate cell survival and programmed cell death.¹⁴⁸ Additionally, the suppression of apoptosis by miR-26a has been demonstrated to be PTEN dependent, regulating the JAK/STAT and PI3K/AKT pathways, thereby providing cardioprotection against myocardial infarction and enhancing cardiac function.¹⁴⁹ A relevant study in bladder cancer demonstrated that inhibition of STAT3 enhances the response to PI3K inhibitors both in vitro and in vivo, resulting in sustained tumor suppression, increased apoptosis, and significant tumor regression.¹⁵⁰

Crosstalk of PI3K/AKT signaling with TGF-β signaling

TGF-β, a multifunctional cytokine, is essential for modulating various cellular processes, including cell proliferation, differentiation, development, and migration.¹⁵¹ Substantial evidence indicates that the TGF-β signaling pathway exhibits dual roles in tumorigenesis, functioning as either a tumor suppressor or a tumor promoter depending on the context.^152,153 In advanced tumor cells, TGF-β activation enhances tumorigenic processes, including cell motility, immune evasion, and metastasis.¹⁵⁴ In contrast, in normal cells and early-stage tumor cells, the TGF-β pathway exhibits tumor-suppressive functions by inhibiting the epithelial cell cycle and promoting apoptosis.¹⁵⁵ TGF-β is synthesized as a latent precursor requiring activation to execute its biological functions.¹⁵⁶ The pro-TGF-β molecule consists of three components: a signal peptide, an extensive prodomain at the N-terminus, and a short fragment at the C-terminus.¹⁵⁷ Upon activation, TGF-β signals through TGF-β type I and type II receptors, with the canonical Smad-dependent pathway serving as the primary signaling route.¹⁵⁸ Impairments in the TGF-β pathway, particularly in epithelial cells, tissue fibroblasts, and immune cells, compromise immune tolerance, induce inflammatory responses, and contribute to fibrosis and tumor development, including resistance to therapeutic interventions.^159,160 In BC, AKT activation leads to the phosphorylation of the transcription factor Twist1, promoting TGF-β2 secretion and enhancing TGF-β signaling. This feedback loop further amplifies AKT activation, thereby facilitating tumor cell invasion and metastasis.¹⁶¹ The overexpression of tensin 4 activates focal adhesion kinase and potentiates the PI3K/AKT signaling pathway, while also facilitating the assembly of the TGFβRI/II complex, and ultimately synergistically activates the TGF-β signaling pathway, thereby contributing to tumorigenesis in head and neck squamous cell carcinoma (HNSCC).¹⁶² Therapeutic strategies targeting the interaction between the PI3K/AKT signaling pathway and the TGF-β signaling pathway may hold potential for clinical applications.

Crosstalk of PI3K/AKT signaling with Notch signaling

The Notch signaling pathway, an evolutionarily conserved cascade, plays a crucial role in multiple developmental processes, such as cell differentiation, tissue development, organogenesis, and the pathogenesis of numerous diseases.¹⁶³ The mammalian Notch pathway comprises three core components: Notch receptors, ligands, and downstream effectors.¹⁶⁴ In Drosophila, a single Notch receptor and two DSL ligands are present, while mammals possess four Notch receptors (Notch1–4) and five Delta/Serrate/Lag-2 ligands (Delta-like1, 3, 4 and Jagged 1, 2).¹⁶⁵ Each Notch receptor is composed of an extracellular domain linked to the transmembrane and intracellular domains via a calcium-dependent, noncovalent bond.¹⁶⁶ Receptor activation occurs through interaction with adjacent cells expressing delta-like or serrate-like ligands, triggering a series of proteolytic cleavages.¹⁶⁴ The interplay between Notch signaling and the PI3K/AKT cascade significantly influences the pathogenesis and progression of various neoplastic conditions.¹⁶⁷ Crosstalk between these pathways modulates cell survival, proliferation, and tumor progression, emphasizing their role in the onset and progression of malignancies. CXCR4, a cell membrane protein belonging to the chemokine receptor family, plays a pivotal role in various cellular processes.¹⁶⁸ In GBM, inhibition of the Notch1 pathway downregulates CXCR4 expression in glioma-initiating cells (GICs), thereby suppressing the PI3K/AKT/mTOR signaling cascade. This inhibition impairs the self-renewal capacity, invasiveness, and tumorigenic potential of GICs.¹⁶⁹ Notch1 has been recognized as a critical oncogenic driver in the development of T-cell lymphoblastic lymphoma (T-LBL). The activation of the Notch/PI3K-AKT signaling pathway, together with alterations in cell cycle regulatory proteins, constitutes a central tumorigenic mechanism in T-LBL.¹⁷⁰ Accumulating evidence indicates that Notch3 promotes the transcription of secreted phosphoprotein 1 (SPP1). Targeted inhibition of Notch3 suppresses tumor growth and metastasis in bladder cancer by modulating the SPP1-PI3K/AKT pathway axis¹⁷¹ Collectively, understanding the complex crosstalk between the PI3K/AKT and Notch signaling pathways not only enhances our mechanistic insights into tumor initiation and progression but also offers valuable implications for the development of targeted therapeutic interventions against cancers driven by these interconnected signaling networks.

Crosstalk of PI3K/AKT signaling with Hedgehog signaling

Secreted proteins of the Hedgehog (Hh) family, initially identified in Drosophila melanogaster, regulate embryonic development and maintain tissue homeostasis in adult organisms.^172,173 While Drosophila has a single Hh and a single Gli protein (Cubitus interruptus, Ci), mammals possess three Hh family members and three Gli proteins (GLI1, GLI 2, GLI 3).^174,175 The Hh signal reception mechanism involves the interaction between Patched, a twelve-domain transmembrane protein, and Smoothened, a seven-domain transmembrane protein from the GPCR family, facilitating Hh signal transmission across the cell membrane.^176,177 Aberrant activation of the Hh signaling pathway outside its physiological context contributes to the development, progression, and therapeutic resistance of various tumors, including basal cell carcinoma, medulloblastoma, and a wide range of solid and hematological malignancies.^178,179 Glioma-associated oncogene 1 (GLI1) is a key component of the Hh pathway. In acute myeloid leukemia, GLI1 modulates drug resistance by controlling the cell cycle through the PI3K/AKT/GSK3/CDK signaling axis.¹⁸⁰ Furthermore, Hh signaling promotes GC metastasis through activation of the PI3K/AKT pathway.¹⁸¹ In pancreatic tumors, Hh pathway inhibition effectively suppresses tumor growth by downregulating the PI3K/AKT axis, highlighting its promise as a therapeutic intervention target.¹⁸²

These interactive networks play a central role in embryonic development, tissue homeostasis, and the progression of diseases, particularly cancer. A thorough understanding of the cross-pathway regulatory mechanisms of PI3K/AKT is crucial not only for unraveling the molecular underpinnings of cell fate determination but also for establishing critical theoretical foundations that support the design of targeted therapeutic approaches.

The PI3K/AKT pathway and tumors

The PI3K/AKT cascade plays a fundamental role in regulating cellular proliferation, differentiation, and development and is integral to numerous biological processes.^125,169 Dysregulation of this signaling pathway has been frequently reported in a wide range of human tumors, including those affecting the reproductive, digestive, respiratory, urinary, and nervous systems, among others (Fig. 2). Such dysregulation is often attributed to genetic and epigenetic alterations in key proteins or regulatory components within the pathway.^11,183 These alterations differ among tumor types, consequently influencing the clinicopathological characteristics and prognostic outcomes of these malignancies (Table 2).

Fig. 2.

The PI3K/AKT signaling pathway and tumors. Aberrant activation of the PI3K/AKT signaling pathway is frequently observed across a broad spectrum of human tumors, including those of the reproductive, digestive, respiratory, urinary, and nervous systems. Variations in key proteins or regulatory factors within this pathway differ among tumor types, influencing clinicopathological characteristics and prognosis. PTEN phosphatase and tensin homolog, PI3K phosphatidylinositol 3-kinase, AKT protein kinase B, PC pancreatic cancer, HCC hepatocellular carcinoma, CRC colorectal cancer, GC gastric cancer, ESCC esophageal squamous cell carcinoma, BC breast cancer, OC ovarian cancer, CC cervical cancer, OSCC oral squamous cell carcinoma, HNSCC head and neck squamous cell carcinoma, PCa prostate cancer, RCC renal cell carcinoma, NSCLC non-small cell lung cancer, SCLC small cell lung cancer. Figure created with BioRender (https://www.biorender.com)

Table 2.

The PI3K/AKT pathway and tumor

Category	Cancer type	Related molecule	Alteration	Expression	Clinical feature	Prognosis	Ref.
Digestive system	Hepatocellular carcinoma	PIK3CA	Mutation	Upregulated	Hepatic steatosis, tumor development	Poor	190
		PIK3CA	/	Upregulated	Proliferation, migration, and growth	Poor	196
		PIK3CD	Mutation	Upregulated	Recurrence, proliferation, and colony formation	Poor	194
		p110γ	/	Upregulated	Cell proliferation and cell cycle	Poor	195
	Colorectal cancer	PIK3CA	Mutation	Upregulated	Apoptosis and tumor invasion, migration, and metastasis	Poor	205
		PIK3CA	Mutation	Upregulated	RFS, OS, disease stage, lymph node involvement, the presence of angiogenesis and neuroinvasion	Poor	207
		FOXO1	/	Upregulated	PFS, vascular invasion, lymph node metastasis, and distant metastasis	Poor	211
		AKT2	/	Downregulated	Cell viability, survival, and motility	Favorable	209
		PTEN	/	Downregulated	Tumor size, advanced tumor stage, and OS	Poor	213
	Gastric cancer	PIK3CA	/	Upregulated	DFS, OS, proliferation, and invasion	Poor	219
		PIK3CA	/	Upregulated	Lymph node metastasis and distant metastasis	Poor	220
		AKT1	Mutation	Upregulated	OS, recurrence	Poor	223
		FOXO1A	/	Upregulated	OS, lymph node metastasis, and apoptosis	Favorable	224
	Esophageal squamous cell carcinoma	FOXO1	/	Upregulated	OS, growth	Poor	230
		PIK3CB	/	Upregulated	Proliferation, the cell cycle, and apoptosis	Poor	232
		PIK3CA	Mutation	/	OS, DFS, PFS	Favorable	231
		PTEN	Mutation	Upregulated	Proliferation, drug resistance and growth	Favorable	237
		pAKT1	/	Upregulated	OS	Poor	233
	Pancreatic cancer	PIK3CA	Mutation	/	Tumorigenesis, OS	Poor	242
		PTEN	/	Upregulated	Survival, proliferation, angiogenesis, and migration	Favorable	244
Reproductive system	Breast cancer	PIK3CA	Mutation	/	Breast epithelial transformation, metastatic progression, and drug resistance	Poor	253
		PIK3CB	Mutation	Upregulated	Drug resistance	Poor	254
		AKT1	Deletion	Downregulated	Tumor metastases, OS	Favorable	256
		AKT2	/	Upregulated	Invasion, metastasis	Favorable	258
	Ovarian cancer	AKT2	/	Upregulated	Invasion, metastasis, vessel formation, survival, and drug resistance	Poor	265
	Cervical cancer	PIK3CA	Mutation	Upregulated	Transformed phenotypes, growth, and differentiation	Poor	269
		AKT1	/	Upregulated	Proliferation, invasion and EMT	Poor	271
Urinary system	Prostate cancer	PTEN	Deletion	Downregulated	Progression, recurrence and RFS	Poor	276
		PIK3CA	Mutation	/	OS, progression, and tumorigenesis	Poor	278
	Bladder cancer	PIK3CA	Mutation	/	Hyperplasia and nuclear atypia	Poor	287
		PTEN	/	Downregulated	Growth, progression, and tumorigenesis	Poor	291
	Renal cell carcinoma	PTEN	Deletion	Downregulated	OS and progression	Poor	296
		AKT3	/	Downregulated	Migration, invasion, metastasis	Poor	298
Respiratory system	Small cell lung cancer	PIK3CA	Mutation	/	Drug resistance, proliferation, and colony formation	/	302
	Non-small cell lung cancer	PIK3CA	Mutation	/	Drug resistance, OS and PFS	Poor	310
		PTEN	Deletion	Downregulated	OS and PFS	Poor	313
		AKT3	/	Upregulated	Drug resistance, cell death and apoptosis	Poor	315
Nervous system	Glioma	PIK3CB	/	Upregulated	Occurrence and OS	Poor	320
		AKT2	/	Upregulated	Invasion, cell survival and migration	Poor	322
		AKT3	/	Downregulated	Progression, occurrence, and drug resistance	Favorable	64
Tumors of other systems	Oral squamous cell carcinoma	PIK3CA	Mutation	/	Drug resistance and cell growth	Poor	333
		AKT2	/	Upregulated	EMT, proliferation and migration	/	334
	Head and neck squamous cell carcinoma	PIK3CA	Mutation	Upregulated	Invasion, migration, inflammation, and progression	Poor	340
		AKT3	/	Upregulated	Immune cell infiltration, OS, proliferation, and apoptosis	Poor	341

Digestive system tumors

Hepatocellular carcinoma (HCC)

HCC is a prevalent malignancy and a leading cause of cancer-related mortality.¹⁸⁴ A comprehensive understanding of its molecular pathogenesis is critical for developing targeted therapies. The pathogenesis of HCC involves a complex interplay of disrupted tumor suppressor genes and oncogenes, aberrant activation of signaling pathways, altered cellular differentiation, and dysregulated angiogenesis.^185,186 Dysregulation of the PI3K/AKT pathway has been extensively documented in HCC.¹⁸⁷ Mutations in PIK3CA, particularly within the helical and kinase domains, have been identified in approximately 4% to 6% of human HCC tumor specimens.¹⁸⁸ Experimental models have demonstrated that activated PIK3CA, when combined with oncogenic factors such as yes-associated protein 1 (YAP1), RasV12, or c-Met, exhibits a hepatocarcinogenic effect.^189,190 The regulatory network both upstream and downstream of the PI3K/AKT pathway further modulates HCC progression. Shp2, an SH2-containing tyrosine phosphatase downstream of receptor tyrosine kinases (RTKs), has been identified as a critical regulator in liver tumors.¹⁹¹ Deletion of Shp2 impedes liver tumorigenesis driven by the co-expression of c-Met and PIK3CA, thereby disrupting the transmission of oncogenic signals in hepatic tissue.¹⁹² In addition to PIK3CA, other PI3K isoforms contribute to HCC pathogenesis. PIK3CD has emerged as a potential biomarker for predicting HCC recurrence.¹⁹³ Studies have shown that silencing PIK3CD expression significantly reduces the colony-forming capabilities of HCC cells in HepG2/C3A and PLC/PRF/5 cell lines.¹⁹⁴ Additionally, the absence of p110γ has been associated with inhibited liver cancer cell growth by inducing cell cycle arrest in the G0-G1 phase.¹⁹⁵ The lncRNA AWPPH has been shown to facilitate the interaction between the multifunctional protein YBX1 and the PIK3CA promoter, thereby enhancing PIK3CA transcription and activating the PI3K/AKT signaling pathway in HCC cells.¹⁹⁶ Similarly, LINC00152 promotes HCC progression by negatively regulating miR-139, leading to enhanced PI3K/AKT pathway activation. These findings indicate that targeting lncRNA-mediated modulation of the PI3K/AKT pathway could present a promising new approach for HCC treatment.¹⁹⁷

Colorectal cancer (CRC)

CRC represents a prevalent and aggressive carcinoma worldwide, characterized by low curative rates and poor prognosis.¹⁹⁸ The primary anatomical subtypes of CRC include tumors located in the colon, proximal colon, distal colon, and rectum.¹⁹⁹ Notably, since 1994, the incidence of CRC among individuals under the age of 45 has shown a consistent annual increase.^200,201 Understanding the molecular mechanisms underlying CRC progression is essential for developing effective prevention strategies and optimizing therapeutic interventions.¹⁰ Numerous studies have established a significant role of the PI3K/AKT cascade in CRC development, where aberrant activation of this pathway is strongly linked to tumor initiation.^202,203 Importantly, mutations in the PIK3CA gene are prevalent in various human cancers, with ~30% of CRC cases harboring these mutations.²⁰⁴ These genetic alterations contribute to tumorigenesis by inhibiting apoptosis and promoting tumor invasion under specific conditions.^205,206 Prolonged AKT activation, resulting from PIK3CA mutations, enhances cellular survival and proliferation. Interestingly, increased PIK3CA gene and protein expression levels have been detected in normal tissues compared to rectal tumors.²⁰⁷ AKT1, known to be significantly upregulated in CRC, is implicated in conferring apoptosis resistance, thereby contributing to tumor persistence.²⁰⁸ In contrast, the absence of AKT2 has been shown to suppress CRC metastasis and impede the early development of colorectal tumors in vivo.²⁰⁹ The AKT kinase is also instrumental in modulating the expression of proteins from the FOXO family, which are key downstream effectors of the PI3K/AKT pathway.²¹⁰ Increased FOXO1 expression has been observed in rectal tumor tissue compared to colonic tumors and is strongly correlated with aggressive tumor phenotypes and reduced survival rates.²¹¹ PTEN, a tumor suppressor protein with phosphatase activity, serves as a key negative regulator of the PI3K/AKT pathway.²¹² Loss of PTEN protein expression has been linked to enhanced tumor progression, invasion, and metastasis, making it a reliable marker of aggressive CRC and an unfavorable prognostic indicator.²¹³

Gastric cancer (GC)

GC is a major global health challenge, being one of the most prevalent and fatal malignancies worldwide.²¹⁴ GC exhibits considerable molecular and phenotypic heterogeneity, reflecting the intricate interplay of genetic, environmental, and lifestyle factors in its pathogenesis.²¹⁵ Key risk factors include Helicobacter pylori infection, advanced age, high salt intake, and a diet deficient in fruits and vegetables.²¹⁶ Due to the asymptomatic nature of early-stage GC, most cases are diagnosed at intermediate or advanced stages, contributing to a low survival rate.²¹⁷ Multiple genetic mutations, particularly involving the PIK3CA gene, have been identified as critical drivers in the development of GC. These mutations activate the PI3K/AKT signaling pathway, thereby enhancing tumorigenic potential.²¹⁸ The PIK3CA gene has been shown to promote invasion in GC cells.²¹⁹ Notably, normal gastric mucosa exhibits minimal PIK3CA expression, whereas significantly elevated levels are observed in lymph node and distant metastases compared to primary GC tissues.²²⁰ Overexpression of AKT genes has been frequently reported in a range of human tumors, including GC.²²¹ Initial studies by Staal and colleagues identified AKT1 amplification in a single GC case, recognizing it as a potential human oncogene.²²² Subsequent research has consistently linked high levels of AKT1 activation with poorer prognostic outcomes in patients with GC, suggesting its role as a negative prognostic marker.²²³ Phosphorylated FOXO1A (pFOXO1A) is a member of the FOXO transcription factor family. Elevated pFOXO1A expression has been associated with the onset of various human tumors, and its presence in early-stage GC is significantly correlated with improved patient prognosis.²²⁴ Given these findings, therapeutic strategies targeting pFOXO1A, PIK3CA, and AKT may effectively inhibit GC cell proliferation and metastasis by disrupting the PI3K/AKT signaling axis. These results underscore the therapeutic potential of modulating the PI3K/AKT pathway as a promising therapeutic approach for GC treatment.

Esophageal squamous cell carcinoma (ESCC)

ESCC is the most prevalent histological subtype of esophageal cancer, arising from the squamous epithelium of the esophagus.²²⁵ It is characterized by its aggressive progression, rapid tumor growth, and high incidence of lymph node metastasis.^225,226 The PI3K/AKT/mTOR pathway plays a pivotal role in ESCC cell proliferation, differentiation, metastasis, and apoptosis.^227,228 Genetic alterations within the PI3K/AKT/mTOR cascade, particularly in the PIK3CA and AKT subtypes, have been identified and are known to activate this pathway, thereby influencing ESCC pathogenesis.^229,230 PIK3CA mutations in ESCC correlate with a positive prognosis, suggesting that PIK3CA mutation status may serve as a reliable biomarker for predicting favorable clinical outcomes in patients.²³¹ Conversely, PIK3CB, which is highly expressed in ESCC, promotes tumor progression via the PI3K/AKT/mTOR axis and is associated with poor prognosis.²³² Elevated activation of AKT1 has also been identified as an independent prognostic factor, as high p-AKT1 expression levels correlate with reduced overall survival (OS).²³³ Further research has demonstrated a strong correlation between periostin and mTOR in locally advanced ESCC, with both factors serving as independent predictors of OS and progression-free survival (PFS).²³⁴ Mutations or functional inactivation of the PTEN gene result in sustained activation of the PI3K/AKT pathway, contributing to tumor formation across various organs and correlating with poor prognosis.^235,236 Experimental evidence has demonstrated that cisplatin exerts potent antitumor effects on EC9706 cells transfected with the wild-type PTEN gene, indicating that PTEN expression enhances the sensitivity of ESCC cells to cisplatin treatment in vivo.²³⁷ These findings underscore the critical role of the PI3K/AKT cascade in ESCC initiation and progression, highlighting the potential of targeting this pathway as a therapeutic strategy.

Pancreatic cancer (PC)

PC is a highly malignant disease with a dismal prognosis and high mortality rate.²³⁸ Most patients present with advanced-stage disease, resulting in limited therapeutic options and low survival rates.²³⁹ Early detection of preinvasive pancreatic neoplasia and identification of molecular targets for therapy are essential for improving patient outcomes.²⁴⁰ The development of PC is closely linked to the activation of the PI3K/AKT pathway. The PIK3CA gene, encoding the p110α catalytic subunit of PI3K, is mutated in ~3–5% of PC cases.²⁴¹ These mutations have been implicated in the initiation and progression of pancreatic tumors.²⁴² PTEN, a key regulator of cell survival signaling via the PI3K/AKT pathway, plays a critical role in modulating angiogenesis in PC.²⁴³ Targeted inhibition of PTEN results in increased secretion of vascular endothelial growth factor (VEGF) from PC cells, thereby enhancing the proliferation of vascular endothelial cells and promoting tumor angiogenesis.²⁴⁴ These results suggest that PI3K/AKT pathway inhibitors hold therapeutic potential for PC, warranting further investigation in clinical settings.

Reproductive system tumors

Breast cancer (BC)

BC is the most frequently diagnosed cancer among women and represents the second leading cause of cancer-related mortality in this population.^245,246 This malignancy is notably heterogeneous, driven by both genetic predisposition and environmental influences.^247,248 Despite advancements in BC treatment, metastasis and recurrence remain formidable challenges.²⁴⁹ Substantial evidence has established the critical role of the PI3K/AKT cascade in these processes. In primary BC, mutations in the PIK3CA gene are prevalent, particularly in hormone receptor-positive tumors.²⁵⁰ These mutations can influence cancer development by modulating estrogen receptor signaling and have also been associated with promoting cellular senescence in BC.^251,252 Preclinical studies suggest that PIK3CA mutations may induce aberrant activation of the PI3K pathway, contributing to resistance against trastuzumab therapy.²⁵³ Additionally, specific mutations in PIK3CB (D1067Y/A/V) within BC cell lines have been identified as drivers of resistance to PI3K inhibitors through hyperactivation of the PI3K pathway, thereby positioning PIK3CB as an oncogene.²⁵⁴ The diverse subtypes of AKT are involved in regulating various malignant characteristics of BC cells, including proliferation, migration, invasion, metastasis, angiogenesis, and stem cell properties.²⁵⁵ AKT1 is predominantly associated with promoting BC cell proliferation and survival while concurrently inhibiting metastatic processes.²⁵⁶ In contrast, AKT2 is primarily linked to enhanced migration, invasion, and chemotaxis, which are critical for the metastatic cascade.^257,258 The role of AKT3 in BC remains less clear, but existing evidence suggests that it may have an antimigratory function.²⁵⁹

Ovarian cancer (OC)

OC is an aggressive malignancy frequently diagnosed at an advanced stage.^260,261 Activation of the PI3K/AKT pathway is a hallmark of OC, contributing to increased cellular proliferation, migration, invasion, and chemotherapy resistance.²⁶² Mutations in the PIK3CA gene, PTEN gene deletions, and amplification of AKT1, AKT2, and AKT3 genes collectively result in abnormal PI3K/AKT pathway activation.²⁶³ Accumulating evidence suggests that miR-337-3p functions as a tumor suppressor in epithelial OC by regulating the expression of p110α and p110β proteins, which are encoded by PIK3CA and PIK3CB, respectively, thereby exerting antitumorigenic effects.²⁶⁴ Upon stimulation by growth factors, AKT1 is activated through phosphorylation at T308 and S473. AKT2 amplification and overexpression are common in OC and are associated with increased invasion, recurrence, and metastasis, particularly in cells exhibiting elevated AKT2 levels.²⁶⁵ Collectively, numerous studies have identified critical connections between components of the PI3K/AKT pathway and the malignant characteristics of OC.

Cervical cancer (CC)

CC ranks as the fourth most common malignancy among women worldwide.²⁶⁶ Human papillomavirus (HPV) infection is implicated in 99.7% of global cases of cervical squamous cell carcinoma, highlighting its pivotal role in CC pathogenesis.²⁶⁷ The PI3K/AKT signaling cascade is frequently activated in HPV-infected cells due to mutations in pathway components and the activation of upstream signaling molecules.²⁶⁸ mRNA expression of the catalytic subunit PIK3CA is significantly upregulated in cervical squamous cell carcinoma.²⁶⁹ Mutations in the PIK3CA gene have been demonstrated to enhance glucose metabolism in CC cells, both in vivo and in vitro.²⁷⁰ Notably, the PIK3CA-E545K mutation has been found to suppress SIRT4 expression, thereby facilitating glutamine metabolism, enhancing DNA damage repair, inhibiting apoptosis, and ultimately reducing radiotherapy sensitivity in CC. In addition to genetic mutations, growth factors also contribute to pathway activation. For instance, growth differentiation factor 15 (GDF15) has been reported to activate the PI3K/AKT pathway through interaction with ErbB2, leading to alterations in cell cycle regulator levels and promoting CC cell proliferation.²⁷¹ Collectively, these findings underscore the integral role of the PI3K/AKT signaling cascade in CC progression. From a therapeutic perspective, targeting the PI3K/AKT pathway may interfere with these pathological processes and represents a promising therapeutic avenue for improving treatment outcomes in CC.

Urinary system tumors

Prostate cancer (PCa)

PCa is the most common noncutaneous malignancy in males globally.²⁷² Despite recent therapeutic advancements, PCa remains a significant health challenge, primarily due to its progression and resistance to treatment.²⁷³ The PI3K/AKT/mTOR pathway is frequently activated in PCa, driving tumor growth, disease progression, and therapeutic resistance.²⁷⁴ Loss of PTEN, a key negative regulator of the PI3K/AKT pathway, is a frequent mutation in primary PCa and serves as a robust predictor of poor biochemical recurrence and reduced recurrence-free survival (RFS).²⁷⁵ In PTEN-deficient PCa cells, survival, metastatic potential, and invasiveness are predominantly driven by AKT2 activation, while AKT3 plays a comparatively minor role. Conversely, restoring PTEN expression suppresses oncogenic activity and shifts dependency toward AKT1.²⁷⁶ Alterations in the PIK3CA gene have also been strongly linked to poor prognostic outcomes in PCa.²⁷⁷ The cooccurrence of PIK3CA mutations and PTEN loss has been observed, and these genetic aberrations synergize to accelerate tumor progression and the development of castration-resistant PCa.^278,279 Moreover, kinesin family member 15 (KIF15) has been identified as a key factor in PCa tumorigenesis. Reducing KIF15 expression has been shown to inhibit subcutaneous tumor growth in PCa cells via the PI3K/AKT signaling pathway.²⁸⁰ Given the complexity of the PI3K/AKT cascade, further research is essential to develop targeted therapeutic strategies aimed at effectively modulating this pathway to prevent and manage PCa.

Bladder cancer

Bladder cancer remains a major cause of cancer-related mortality globally, significantly affecting patient quality of life, disease burden, survival outcomes, and healthcare costs.²⁸¹ Epidemiological studies have identified that the predominant risk factors for bladder cancer include smoking and occupational exposure to carcinogenic substances.²⁸² Although bladder cancer is more common in men, women are more likely to be diagnosed at a late stage, leading to a poorer prognosis.²⁸³ The PI3K/AKT signaling pathway has been extensively implicated in the progression of bladder cancer.^284,285 Mutations in the PIK3CA gene have been identified in bladder cancer, where PIK3CA can trigger early tumorigenic changes in the urothelium.²⁸⁶ However, additional genetic alterations are typically required for the progression to invasive carcinoma.²⁸⁷ Downregulation of PTEN, a key negative regulator within the PI3K/AKT pathway, is associated with poor prognosis in patients with bladder cancer, facilitating increased cell migration and invasion.²⁸⁸ Moreover, loss of PTEN contributes to chemotherapy resistance, as bladder cancer cells with reduced PTEN expression demonstrate diminished apoptotic and cell cycle arrest responses to chemotherapeutic agents.^289,290 The degradation of the PTEN protein, resulting from decreased ubiquitin-specific peptidase 8 (USP8) mRNA expression, compromises the stability of urothelial cells and predisposes them to basal-muscle invasive bladder cancer.²⁹¹ These insights underscore the vital role of the PI3K/AKT pathway in bladder cancer pathogenesis, suggesting that targeting this signaling axis could enhance therapeutic outcomes for patients with bladder cancer.

Renal cell carcinoma (RCC)

RCC is a malignant tumor originating from the urinary system, with a steadily increasing global incidence.²⁹² Clear cell renal cell carcinoma (ccRCC) accounts for ~60–70% of RCC cases.²⁹³ The PI3K/AKT signaling pathway plays a pivotal role in RCC development, metastasis, and treatment resistance. Research has highlighted the prognostic value of PI3K/AKT-related proteins in RCC, noting that PTEN expression is significantly lower in RCC than in normal renal tissue, while phosphorylated AKT (p-AKT) levels are markedly higher.^294,295 The activation of AKT is significantly more pronounced in RCC than in normal kidney tissue.²⁹⁶ Brusatol, a pharmacological compound studied by Wang and colleagues, has demonstrated the ability to upregulate PTEN expression, inhibit AKT phosphorylation, and subsequently suppress the proliferation, migration, and invasion of RCC cells.²⁹⁷ Furthermore, the circRNA circ-AKT3, originating from the AKT3 gene locus, has been identified as significantly reduced in ccRCC.²⁹⁸ Decreased circ-AKT3 expression promotes ccRCC cell migration and invasion, while overexpression of circ-AKT3 impedes metastatic potential.²⁹⁸ Taken together, these findings offer novel insights into the PI3K/AKT pathway in RCC and suggest that modulation of this signaling pathway could represent an innovative therapeutic strategy for RCC.

Respiratory system tumors

Small cell lung cancer (SCLC)

SCLC is a highly aggressive neuroendocrine malignancy originating from lung neuroendocrine stem cells, accounting for ~13–15% of all lung cancer cases.²⁹⁹ It is characterized by rapid growth, early dissemination, high mortality rates, and an unfavorable clinical outlook.³⁰⁰ The PI3K/AKT signaling cascade plays a critical role in the progression and tumorigenesis of SCLC.³⁰¹ For the first time, PIK3CA mutations have been identified in SCLC, revealing that SCLC cells harboring these mutations demonstrate heightened sensitivity to the AKT inhibitor triciribine compared to cells with wild-type PIK3CA.³⁰² Furthermore, Jin and colleagues discovered that chemotherapy-resistant SCLC cell lines exhibited a reversal of resistance upon inhibition of the PI3K pathway, suggesting that targeting this pathway may overcome chemotherapy resistance.³⁰³ Additional studies have established that PI3K/mTOR signaling significantly contributes to both primary and acquired radioresistance in SCLC.³⁰⁴ These findings suggest that activation of the PI3K/AKT pathway may play a role in therapeutic resistance in SCLC, indicating that targeting this pathway could enhance the effectiveness of current treatment strategies.

Non-small cell lung cancer (NSCLC)

NSCLC is the primary contributor to cancer-related mortality in humans, accounting for ~85% of lung cancer cases.^305,306 The pathogenesis of NSCLC involves complex interactions between genetic factors, including abnormal gene expression, dysregulation of PI3K and AKT family members, and disruptions in molecules that regulate the PI3K/AKT pathway.³⁰⁷ Somatic mutations and amplification of the PIK3CA gene, as well as homozygous and heterozygous PTEN gene deletions and upregulation of the AKT pathway, are frequently observed in patients with NSCLC.^308,309 PIK3CA mutations occur in ~5–8% of NSCLC cases, with the E545K mutation being the most common.³¹⁰ PIK3CA mutations have been identified as independent risk factors for OS and PFS in patients with surgically resected lung adenocarcinoma.³¹¹ Moreover, mutations in the PIK3CA gene can induce resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC cases.³¹⁰ The absence or low expression levels of PTEN have been established as significant independent prognostic indicators in NSCLC.³¹² PTEN deletion markedly reduces the sensitivity of EGFR-mutant NSCLC cells to apoptosis by concurrently activating the AKT and EGFR pathways.³¹³ Additionally, AKT subtypes exhibit distinct roles in NSCLC pathology: silencing AKT1 promotes NSCLC cell migration, while knockdown of AKT2 exerts no significant effects on this cellular behavior.³¹⁴ In contrast, targeted suppression of AKT3 using shRNA has been shown to induce apoptosis in H1975OR cells, whereas overexpression of AKT3 reduces the sensitivity of H1975 NSCLC cells, underscoring its role in resistance mechanisms.³¹⁵ Given the intricate involvement of the PI3K/AKT pathway in both SCLC and NSCLC, elucidating its molecular mechanisms is vital for developing targeted treatment therapies.

Nervous system tumors

Glioma

Gliomas, the most prevalent primary neoplasms of the central nervous system, originate from glial progenitor cells and are typically associated with poor clinical outcomes.³¹⁶ The PI3K signaling pathway, known for promoting cellular proliferation and survival, is frequently upregulated in aggressive gliomas.^317,318 Among the PI3K catalytic subunits, the PIK3CA mutation distinctly drives increased brain activity during glioma progression and is associated with early recurrence and diminished survival in adult glioblastoma.³¹⁹ Notably, PIK3CB/p110β emerges as the sole PI3K subtype significantly correlated with increased incidence, heightened risk, and reduced survival in recurrent GBM, while the roles of PIK3CD/PI3Kδ and PIK3CG/PI3Kγ in GBM remain inadequately explored, likely due to their predominant association with hematopoietic pathologies.^320,321 High-grade gliomas exhibit marked upregulation of the AKT2 gene, which enhances glioma cell migration and invasion by regulating cytoskeletal dynamics and modulating cell adhesion.^322,323 Additionally, AKT3 exerts a pivotal influence on glioma progression by activating DNA repair pathways, thereby conferring increased resistance to radiation and temozolomide.⁶⁴ Recent advances have further elucidated the central role of the PI3K signaling pathway in glioma heterogeneity, treatment resistance, and therapeutic targeting. Notably, IDH-mutant lower-grade gliomas, which exhibit relatively indolent clinical behavior, frequently harbor concurrent alterations in the PI3K/AKT/mTOR axis, suggesting a contributory role in early glioma genesis and tumor progression.³²⁴ In glioblastoma, activation of the PI3K pathway commonly coexists with PTEN loss or EGFR amplification, leading to constitutive AKT signaling and metabolic reprogramming that supports tumor growth and immune evasion.³²⁵ From a therapeutic perspective, both pan-PI3K and isoform-selective inhibitors, such as buparlisib and alpelisib, have shown limited single-agent efficacy in GBM, primarily due to the development of adaptive resistance mechanisms. However, combinatorial strategies involving PI3K inhibitors with mTOR inhibitors, MEK inhibitors, or immune checkpoint blockade are currently being evaluated in clinical trials.^326,327 Moreover, modulation of the PI3K pathway could potentiate the efficacy of tumor-treating fields (TTFs) and targeted immunotherapies, including CAR-T cells directed against EGFRvIII and IL13Rα2, by reshaping the tumor microenvironment and improving T-cell infiltration.³²⁸ These findings underscore the therapeutic significance of PI3K signaling not only as a driver of glioma progression but also as a rational target for next-generation multimodal treatment approaches. Overall, the PI3K/AKT signaling axis plays a critical role in glioma cell fate determination.

Tumors of other systems

Oral squamous cell carcinoma (OSCC)

OSCC represents the most common subtype of oral cancer, accounting for ~80% of cases.³²⁹ Characterized by its aggressive malignancy, OSCC exhibits high incidence and mortality rates.³³⁰ Elucidating the underlying mechanisms of OSCC is crucial for advancing targeted therapeutic approaches.³³¹ Genomic profiling of OSCC has identified PIK3CA as a significantly mutated oncogene.³³² Evidence indicates that PIK3CA mutations confer resistance to palbociclib in OSCC cell lines, while inhibition of PI3K signaling restores palbociclib sensitivity in OSCC models.³³³ Furthermore, elevated expression of AKT2 and p-AKT has been observed in OSCC, underscoring their pivotal role in cancer development and suggesting the possibility of posttranscriptional modifications of AKT2 in OSCC.³³⁴ Despite limited insights into the involvement of the PI3K/AKT axis in OSCC, comprehensive investigations are required to resolve the ambiguous role of PI3K/AKT signaling in OSCC pathogenesis.

Head and neck squamous cell carcinoma (HNSCC)

HNSCC mainly originates in the mucosal epithelium of the oral cavity, pharynx, and larynx and is frequently associated with carcinogen exposure from tobacco and excessive alcohol consumption.^335,336 Ranking as the sixth most common cancer worldwide, HNSCC demonstrates a strong connection between the PI3K/AKT signaling pathway and its initiation and progression.^337,338 PIK3CA has emerged as a commonly altered oncogene in HNSCC.³³⁹ Increased PIK3CA expression has been linked to enhanced invasion and dissemination of HNSCC through the facilitation of EMT and the potential expansion of cancer stem cell populations in the head and neck region.³⁴⁰ Akt activation is a prevalent feature in HNSCC, with AKT3 expression markedly elevated in HNSCC tissues compared to normal counterparts, correlating with immune cell infiltration and poor prognosis.³⁴¹ Additional research is essential to substantiate the therapeutic promise of inhibiting the PI3K/AKT signaling cascade in HNSCC, as improving prognostic outcomes necessitates more comprehensive insight into disease biology, identification of novel predictive biomarkers, and exploration of viable therapeutic targets.

Mechanism of tumorgenesis and progression mediated by the PI3K/AKT signaling pathway

Compared to other signaling pathways, the PI3K/AKT signaling pathway exhibits unique regulatory mechanisms and biological functions that are critically relevant in tumor biology. It serves as a fundamental regulator of tumor initiation and progression, influencing diverse processes, including EMT, metabolic reprogramming, angiogenesis, programmed cell death, tumor microenvironment (TME) modulation, and resistance to therapeutic agents.^10,342 Comprehensive analysis of these mechanisms may yield innovative perspectives on the development of targeted treatments for multiple cancer types (Table 3).

Table 3.

Mechanism of tumorigenesis and progression mediated by PI3K/AKT pathway

Involved biological process	Cancer	Related molecule	Mechanism	Ref.
EMT	Oral cancer	PI3K, AKT, m-TOR, E-cadherin, N-cadherin, LYC	p-PI3K/PI3K, p-AKT/AKT, and p-m-TOR/m-TOR ↓ → E-cadherin/N-cadherin ↑ →PI3K/AKT signaling ↓ →EMT ↓ →apoptosis↑	353
	Ovarian cancer	E-cadherin, Snail	E-cadherin ↓ →EMT	354
	Colorectal cancer	E-cadherin, N-cadherin, Snail 1, MMP-9, PCSK9	Snail 1 ↑ → E-cadherin ↓ →N-cadherin ↑ →MMP-9 ↑ → EMT	355
Metabolic reprogramming	Colorectal cancer	P-PI3K, p-AKT-HIF-1α, ROS	ROS → HIF-1α ↑ → PI3K/AKT signaling pathway →metabolic reprogramming	367
	Hepatocellular cancer	VersicanV1, EGFR	VersicanV1→EGFR-PI3K-AKT signaling →Warburg effect ↑ →proliferation, invasion, and metastasis of HCC cells↑	370
	Hepatocellular cancer	CD36, mTOR, Src	CD36→Src/PI3K/AKT signaling axis →mTOR phosphorylation ↑ →glycolytic ↑ →growth and metastasis↑	371
	Breast cancer	Zeb1, PI3K, AKT, HIF-1α	Zeb1 → PI3K/Akt/HIF-1α signaling axis →glycolytic activity	369
	Glioblastoma	POU2F2, PI3K, AKT	POU2F2 → PI3K/AKT pathway →aerobic glycolysis↑	372
	Ovarian cancer	SIK2, HIF-1α	PI3K/AKT signaling pathway→HIF-1α ↑ →glycolysis↑	366
Drug resistance	Pancreatic cancer	circACTR2, miR-221-3p, PTEN	PTEN expression ↑ → PI3K/AKT signaling pathway ↓ →gemcitabine resistance↓	378
	Pancreatic cancer	FTO, NEDD4, PTEN	FTO ↓ → PTEN ↑ → PI3K/AKT pathway→ gemcitabine resistance in PC cells↑	376
	Hepatocellular cancer	ANXA3, HIF	ANXA3→intrinsic apoptotic pathways, ERK, and PI3K/AKT-HIF→ malignant behaviors, angiogenesis, and chemoresistance	384
	Breast cancer	14, 15-EET, αvβ3, FAK, PI3K, AKT	14, 15-EET/ αvβ3/FAK/PI3K/AKT pathway→ EMT→ resistance to cisplatin	386
	Gastric cancer	ANXA1, PI3K, AKT	Promote resistance ↑ →autophagy ↑ →PI3K/AKT signaling pathway↓	380
	Gastric cancer	FOXD1-AS1, PIK3CA, miR-466	FOXD1-AS1→miR-466 ↓ → PIK3CA ↑ → PI3K/AKT/mTOR signaling pathway→ resistance to cisplatin	381
	Osteosarcoma	ZIP10, CREB, ITGA10	ZIP10 → CREB-ITGA10-PI3K/AKT signaling pathway →cell growth and resistance to chemotherapy	387
Tumor angiogenesis	Gastric cancer	VEGF, PI3K, AKT	VEGF ↓ → PI3K/AKT/mTOR pathway ↓ → tumor growth and angiogenesis	396
	Colorectal cancer	4’-HW, VEGF, PI3K, AKT	4 ‘-HW → VEGF → PI3K/AKT signaling pathway→ angiogenesis↓	397
	Colorectal cancer	CPT, p-PI3K, p-AKT, HIF-1α	p-PI3K, p-AKT and p-mTOR ↓ →nuclear expression ↓ →intracellular HIF-1α ↓ →the growth, invasion, inflammation, and angiogenesis of CRC	399
	Pancreatic cancer	PTEN, VEGF	PTEN ↓ → VEGF ↑ →angiogenesis, proliferation and migration↑	244
	Ovarian cancer	EPC, MMP-2, PI3K, AKT, Id1	Id1→MMP-2 ↑ → NF-κB → AKT → PI3K → EPC angiogenesis	395
Immune evasion	Thyroid cancer	PD-L1, CD133, AKT	PD-L1 ↑ → CD133-AKT pathway ↑ →self-renewal and immune evasion↑	411
	Hepatocellular cancer	FGF19, FGFR4, PI3K, AKT, PD-L1	PD-L1 ↑ → PI3K/AKT pathway ↓ →proliferation and invasion of HCC↑	412
	Colorectal cancer	COX-2, PGE2, PD-1	PGE2 → PD-1 → PI3K-AK pathway→ cytotoxic activity of CD8 T cells ↓ →phagocytic ↓ →tumor immune evasion↑	410
	Gastric cancer	TGF-β1, HER2, MMP-9, ICAM-1	Harbor HER2 → NF-κB ↑ → ICAM-1 and MMP-9 ↑ →tumor immune evasion↑	414
	Non-small cell lung cancer	PD-L1, MUC3A	MUC3A → EGFR stability→PI3K/AKT and MAPK pathways ↓ →decreases PD-L1 ↓ →immune evasion	415

PI3K/AKT signaling in EMT

EMT, originally described by Elizabeth Hay in 1982, is an intrinsic cellular process occurring spontaneously across diverse tissues and developmental stages.³⁴³ Characterized by the loss of epithelial characteristics and the acquisition of migratory and invasive properties, EMT is driven by cytoskeletal reorganization and biochemical modifications, leading to the mesenchymal phenotype typical of developmental morphogenesis.^344,345 In the context of cancer, however, EMT extends beyond mere enhancement of migration and invasion.³⁴⁶ It represents a complex reprogramming process that integrates metabolic, epigenetic, and differentiation changes.³⁴⁷ EMT is integral to numerous biological functions, including wound healing, tissue regeneration, organ fibrosis, and cancer progression.^348,349 Accumulating evidence indicates that EMT modulates these processes through multiple signaling cascades, with the PI3K/AKT pathway playing a pivotal role in orchestrating such regulatory networks (Fig. 3).

Fig. 3.

PI3K/AKT signaling pathway in EMT. EMT is integral to biological processes such as wound healing, tissue regeneration, organ fibrosis, and cancer progression. Extensive research has demonstrated that the PI3K/AKT signaling pathway regulates EMT-driven mechanisms across various tumor systems. PI3K phosphatidylinositol 3-kinase, AKT protein kinase B, EMT epithelial–mesenchymal transition, HPIP hematopoietic PBX-interacting protein, PCSK9 proprotein convertase subtilisin/kexin type 9, MMP-9 matrix metalloproteinase-9. Figure created with BioRender (https://www.biorender.com)

The PI3K/AKT signaling pathway is extensively implicated in the EMT of various malignant tumors, including prostate cancer, multiple myeloma, and CRC.¹⁰ Evidence suggests that the interaction between apolipoprotein C-II and CD36 modulates EMT via the PI3K/AKT pathway, thereby facilitating tumor progression and peritoneal metastasis in GC.³⁵⁰ A hallmark of EMT, cadherin switching—characterized by increased N-cadherin expression and decreased E-cadherin expression—is strongly associated with tumor advancement.^351,352 In oral cancer, Wang et al. reported that lycopene treatment significantly reduced the levels of p-PI3K, p-AKT, and p-mTOR in a dose-dependent manner while enhancing E-cadherin, indicating that PI3K/AKT pathway inhibition can suppress EMT and promote apoptosis in oral cancer cells.³⁵³ In OC, the hematopoietic PBX-interacting protein activates the PI3K/AKT pathway, resulting in decreased E-cadherin levels and stabilization of Snail in OC-derived OAW42 cells.³⁵⁴ Snail, a key EMT inducer, downregulates E-cadherin, thereby promoting EMT.³⁵⁵ Furthermore, in CRC, PCSK9 has been identified as an inducer of EMT by elevating Snail 1 expression, reducing E-cadherin levels, and increasing N-cadherin and MMP-9 expression, thereby activating the PI3K/AKT pathway and promoting EMT in colon cancer cells.³⁵⁵ Collectively, these findings underscore the pivotal role of PI3K/AKT signaling in EMT regulation, highlighting that modulating specific proteins within the PI3K/AKT cascade and EMT markers can either promote or inhibit EMT in various tumor types.

PI3K/AKT signaling pathway in cancer metabolism reprogram

Metabolic reprogramming, characterized by enhanced biosynthesis of macromolecules, altered energy metabolism, and maintenance of redox homeostasis, constitutes a fundamental hallmark of cancer, facilitating uncontrolled cell proliferation.³⁵⁶ This complex process involves the activation of multiple signaling pathways, transcription factors, and metabolic enzymes.^357,358 In normal differentiated cells, mitochondrial oxidative phosphorylation predominantly generates the energy and biomolecules required for cellular functions, thereby restraining abnormal cell growth. In contrast, cancer cells primarily depend on aerobic glycolysis, a phenomenon known as the “Warburg effect” first identified in the 1920s.³⁵⁹ The Warburg effect exemplifies metabolic reprogramming in cancer, where cells exhibit increased glucose uptake and lactate production despite sufficient oxygen availability.³⁶⁰ The PI3K/AKT signaling cascade is critically involved in regulating metabolic remodeling in tumor cells (Fig. 4). Numerous studies have demonstrated that AKT activation significantly promotes aerobic glycolysis, rendering cancer cells highly dependent on glucose for survival.^361,362 As a central kinase, AKT activates several downstream effectors critical to metabolic modulation, including mTORC1, GSK3, and the FOXO family of transcription factors.⁵⁹ Among these, mTORC1 activation is frequently observed in rapidly proliferating cancer cells and is integral to metabolic reprogramming.³⁶³ GSK3, which negatively regulates growth factors and insulin signaling through AKT-mediated phosphorylation, becomes functionally suppressed upon AKT activation. Consequently, phosphorylation of GSK3 mitigates its downstream inhibitory effects, thereby contributing to the carcinogenic transformation of cells in response to PI3K/AKT signaling.³⁶⁴

Fig. 4.

PI3K/AKT signaling pathway in cancer metabolism reprogramming. Metabolic reprogramming, a multifaceted process involving signaling pathway activation, transcription factor modulation, and enzyme regulation, is critically driven by the PI3K/AKT cascade within cancer cells. PI3K phosphatidylinositol 3-kinase, AKT protein kinase B, PDK1 phosphoinositide-dependent kinase-1, mTORC1 mammalian target of rapamycin complex 1, HIF-1α hypoxia-inducible factor 1α, Zeb1 zinc finger E-box binding homeobox 1, ROS reactive oxygen species, POU2F2 POU Class Homeobox 2, CD36 cluster of differentiation 36, Rheb Ras homolog protein enriched in brain. Figure created with BioRender (https://www.biorender.com)

The transcription factor hypoxia-inducible factor 1α (HIF-1α) is a critical regulator of glycolysis and tumor growth in hypoxic environments.³⁶⁵ In OC, salt-inducible kinase 2 has been shown to upregulate HIF-1α expression through activation of the PI3K/AKT cascade, thereby directly inducing key glycolytic genes to enhance glycolysis.³⁶⁶ In CRC, ROS accumulation in 5-fluorouracil-resistant cells activates the PI3K/AKT pathway, resulting in HIF-1α upregulation and metabolic reprogramming characteristic of drug resistance.³⁶⁷ In BC, zinc finger E-box binding homeobox 1 (Zeb1) directly enhances the transcription of glycolytic rate-limiting enzymes, including HK2, PFKP, and PKM2, thereby promoting the Warburg effect and contributing to cell proliferation, migration, and chemoresistance.³⁶⁸ Zeb1 functions mechanistically through the PI3K/AKT/HIF-1α axis, facilitating glycolysis under hypoxic conditions and contributing to the formation of an immunosuppressive TME.³⁶⁹

In HCC, VersicanV1, an extracellular matrix protein, augments the Warburg effect in HCC cells via the EGFR-PI3K-AKT signaling pathway, promoting proliferation, invasion, and metastasis.³⁷⁰ Additionally, overexpression of cluster of differentiation 36 (CD36) induces Src phosphorylation, subsequently activating PI3K and AKT. Mechanistically, CD36-mediated Src/PI3K/AKT activation leads to mTOR phosphorylation, enhancing glycolysis and supporting HCC growth and metastasis.³⁷¹ In GBM, POU Class Homeobox 2 (POU2F2) depletion results in cell cycle arrest. POU2F2 is implicated in the metabolic transition from oxidative phosphorylation to aerobic glycolysis by activating the PI3K/AKT cascade, thus promoting glycolytic adaptation and tumor progression.³⁷² These findings indicate that modulating the PI3K/AKT pathway, HIF-1α, and associated molecular regulators significantly impacts glucose uptake, lactate production, and other glycolytic processes, presenting a viable therapeutic strategy for targeting metabolic vulnerabilities in cancer.

PI3K/AKT signaling pathway in drug resistance

Drug resistance remains a major challenge in cancer therapy, often resulting in treatment failure and poor clinical outcomes.³⁷³ Mechanisms of resistance encompass alterations in drug efflux, glycolysis, ferroptosis, cuproptosis, autophagy, apoptosis, DNA damage response, and various signaling pathways, all of which influence cancer progression.^374,375 While the molecular basis of drug resistance is not yet fully elucidated, substantial evidence implicates the PI3K/AKT signaling cascade as a key driver of resistance (Fig. 5).^376,377

Fig. 5.

PI3K/AKT signaling pathway in drug resistance. The PI3K/AKT pathway plays a fundamental role in the development of resistance to anticancer drugs. Investigating the molecular mechanisms underlying this resistance is essential for enhancing therapeutic efficacy in oncology. PI3K phosphatidylinositol 3-kinase, AKT protein kinase B, EGFR epidermal growth factor receptor, PTEN phosphatase and tensin homolog, FAK focal adhesion kinase, ITGA10 integrin α10, ANXA1 annexin A1, ANXA3 annexin A3, HIF hypoxia-inducible factor, FTO fat mass and obesity-associated protein, NEDD4 neuronally expressed developmentally downregulated 4. Figure created with BioRender (https://www.biorender.com)

Drug resistance represents a critical obstacle in the treatment of PC. Studies have identified circACTR2 as a competing endogenous RNA that sequesters miR-221-3p, leading to increased PTEN expression. This upregulation inhibits the PI3K/AKT signaling cascade and decreases gemcitabine resistance in PC cells.³⁷⁸ Conversely, knockdown of fat mass and obesity-associated protein (FTO) significantly enhances PTEN expression by modulating NEDD4, thereby influencing the PI3K/AKT pathway and decreasing gemcitabine resistance.³⁷⁶ Additionally, 6-P exhibits anticancer properties by inhibiting PC cell function, primarily through the suppression of EGFR expression and inactivation of the PI3K/AKT pathway via EGFR degradation through ubiquitination. These findings suggest that 6-P holds potential as a therapeutic agent against PC.³⁷⁹ Similarly, drug resistance is a major challenge in GC. The chemoresistance-associated gene ANXA1 has been implicated in oxaliplatin resistance through the activation of autophagy, a process dependent on the inhibition of the PI3K/AKT signaling cascade.³⁸⁰ Furthermore, FOXD1-AS1 has been shown to sequester miR-466, thereby releasing PIK3CA and activating the PI3K/AKT/mTOR signaling axis. This activation contributes to GC progression and cisplatin (DDP) resistance.³⁸¹

In HCC, chemoresistance is a multifaceted process significantly influenced by dysregulation of the PI3K/AKT signaling pathway. Sorafenib, the first-line treatment for advanced HCC, faces increasing resistance.^382,383 Research has shown that Annexin A3 (ANXA3) enhances malignant phenotypes, angiogenesis, and chemoresistance in HCC cells through the activation of intrinsic apoptotic pathways, ERK, and PI3K/AKT-HIF signaling.³⁸⁴ The PI3K/AKT cascade also mediates drug resistance in other cancer types, such as BC and osteosarcoma. In BC, the lipid signaling molecule 14,15-epoxyeicosatrienoic acid (14,15-EET) modulates various physiological processes.³⁸⁵ Inhibition of 14,15-EET or the integrin αvβ3/FAK/PI3K/AKT cascade has been proposed as a strategy to counteract EMT and cisplatin resistance.³⁸⁶ In osteosarcoma, the zinc transporter ZIP10 enhances cellular proliferation and chemoresistance via activation of the CREB-ITGA10-PI3K/AKT signaling pathway.³⁸⁷

PI3K/AKT signaling pathway in tumor angiogenesis

The concept of angiogenesis in tumor growth, first introduced by Judah Folkman in 1971, refers to the formation of new microvessels from preexisting blood vessels through the migration and proliferation of vascular endothelial cells.^388,389 Similar to normal cells, tumor cells rely on oxygen and nutrients supplied by the vascular system for growth and survival.³⁹⁰ The PI3K/AKT signaling cascade is critically involved in controlling angiogenesis and serves as a central regulator of endothelial cell proliferation, migration, and tube formation.^391,392 A comprehensive understanding of the PI3K/AKT pathway and its mechanism in stimulating tumor angiogenesis is essential for optimizing strategies to effectively inhibit the angiogenic response in tumors (Fig. 6).

Fig. 6.

PI3K/AKT signaling pathway in tumor angiogenesis. The PI3K/AKT cascade is a key regulator of angiogenesis, influencing endothelial cell proliferation, migration, and tube formation. A comprehensive understanding of this pathway’s role in tumor angiogenesis is essential for devising strategies to effectively inhibit vascular growth in tumors. PI3K phosphatidylinositol 3-kinase, AKT protein kinase B, VEGF vascular endothelial growth factor, PTEN phosphatase and tensin homolog, HIF-1α hypoxia-inducible factor 1α, CPT cryptotanshinone, VRAP VEGFR-related protein. Figure created with BioRender (https://www.biorender.com)

Endothelial cell migration, a critical step in angiogenesis, is often initiated by VEGF. The expression level of VEGF in cells and tissues serves as an indicator of angiogenesis.³⁹³ Consequently, inhibiting tumor angiogenesis could prevent tumor growth and metastasis.³⁹⁴ In PC, suppression of PTEN has been linked to increased VEGF secretion by PC cells, thereby promoting angiogenesis.²⁴⁴ In OC, endothelial progenitor cells (EPCs) significantly contribute to tumor angiogenesis and growth. Su et al. reported that the inhibitor of DNA binding/differentiation 1 (ID1) upregulates matrix metalloproteinase-2 (MMP-2) expression through an NF-κB-dependent mechanism and activates the AKT pathway via PI3K, thereby promoting EPC-mediated angiogenesis.³⁹⁵ Moreover, the diterpene tanshinone has been shown to modulate VEGF expression through the PI3K/AKT/mTOR pathway, inhibiting tumor angiogenesis and growth, thus representing a potential therapeutic option for GC.³⁹⁶ Emerging evidence highlights the pivotal role of dysregulated angiogenesis in CRC. A study demonstrated that 4’-hydroxywogonin suppresses VEGF expression and inhibits the PI3K/AKT pathway, effectively reducing angiogenesis in CRC and positioning itself as a promising therapeutic candidate.³⁹⁷ HIF-1α serves as a master regulator of tumor angiogenesis.³⁹⁸ Cryptotanshinone (CPT) has been reported to inhibit the PI3K/AKT/mTOR cascade by decreasing the phosphorylation levels of PI3K, AKT, and mTOR while simultaneously reducing nuclear expression but increasing overall HIF-1α levels. This dual modulation results in the suppression of growth, invasion, inflammation, and angiogenesis in CRC.³⁹⁹

PI3K/AKT cascade in tumor immune evasion

Tumor development is intrinsically linked to immune function, with impaired or suppressed immunity significantly increasing the risk of tumorigenesis.⁴⁰⁰ A hallmark of cancer is its ability to evade immune surveillance, enabling tumor cells to persist and proliferate despite host immune defenses.⁴⁰¹ Tumor immune evasion encompasses a range of mechanisms through which tumor cells escape detection and elimination by the immune system, thereby sustaining uncontrolled growth.⁴⁰² Elucidating the underlying mechanisms of tumor immune evasion is crucial for the development of innovative immunotherapeutic strategies.⁴⁰³ Several immune evasion mechanisms have been identified, including antigen loss, suppression of immune responses by tumor-derived factors, immune escape through tumor cell leakage, lack of costimulatory signals on the tumor cell surface, and the antiapoptotic effects mediated by tumor cells.^404,405 Genetic mutations associated with tumorigenesis frequently alter signaling pathways within tumor cells, such as the PI3K/AKT cascade, consequently affecting both the biological characteristics of the tumor and its immunogenic profile (Fig. 7).

Fig. 7.

PI3K/AKT cascade in tumor immune evasion. Tumor immune escape mechanisms, including antigen loss, immune suppression, leakage-mediated escape, deficient costimulatory signaling, and antiapoptotic effects, often arise from mutations affecting the PI3K/AKT pathway. Such disruptions alter tumor biology and immunogenicity, facilitating immune evasion. PI3K phosphatidylinositol 3-kinase, AKT protein kinase B, COX-2 cyclooxygenase enzymes 2, PGE2 prostaglandin E2, PD-1 programmed cell death protein 1, PD-L1 programmed death-ligand 1, EGFR epidermal growth factor receptor, M-CSF macrophage-colony stimulating factor, HER2 human epidermal growth factor receptor-2, ICAM-1 intercellular adhesion molecule-1, MMP-9 matrix metalloproteinase-9, NF-κB, nuclear factor-kappaB. Figure created with BioRender (https://www.biorender.com)

Inactivation or mutation of the PTEN gene leads to the inactivation of a critical negative regulator of AKT, resulting in the upregulation of programmed death ligand 1 (PD-L1) in cancer.⁴⁰⁶ The binding of programmed cell death protein 1 (PD-1) to PD-L1 or PD-L2 inhibits T-cell proliferation and effector functions, ultimately inducing apoptosis.⁴⁰⁷ Within the TME, T cells display elevated PD-1 levels, which stimulate PD-L1 expression through cytokine release, including IFN-γ, TNF-α, and IL.⁴⁰⁸ The subsequent increase in PD-L1 expression suppresses T-cell cytotoxicity and activation and promotes immune tolerance.⁴⁰⁹ In CRC, the inflammatory mediator and tumor promoter COX-2-derived prostaglandin E2 (PGE2) plays a pivotal role in immune evasion.⁴¹⁰ Mechanistically, PGE2 induces PD-1 expression via the PI3K/AKT pathway, inhibiting the cytotoxic function of CD8⁺ T cells and impairing the ability of macrophages to phagocytize tumor cells, thereby facilitating tumor immune escape.⁴¹⁰ In thyroid cancer, acetylcholine activation of the CD133-AKT signaling axis enhances PD-L1 expression, leading to increased resistance of CD133⁺ cells to CD8⁺ T-cell-mediated cytotoxicity. This interaction promotes the self-renewal and immune evasion of CD133⁺ thyroid cancer cells.⁴¹¹ Additionally, the interaction between fibroblast growth factor 19 (FGF19) and fibroblast growth factor receptor 4 (FGFR4) in HCC induces insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)-mediated upregulation of PD-L1 while concurrently suppressing the PI3K/AKT pathway, thereby promoting cell proliferation and invasion. Combining FGFR4 inhibition with anti-PD-1 antibodies has demonstrated efficacy in suppressing tumor progression and enhancing the therapeutic response to immunotherapy.⁴¹² In BC, endoplasmic reticulum stress triggers the release of exosomes containing miR-27a-3p, which subsequently enhances PD-L1 expression in macrophages.⁴¹³ This mechanism, mediated through the PTEN-AKT/PI3K pathway, facilitates BC cell immune evasion. In GC, the TGF-β1-induced PI3K/AKT/NF-κB signaling cascade plays a significant role in tumor progression and represents a potential therapeutic target. GC cells harboring the human epidermal growth factor receptor-2 (HER2) oncogene activate NF-κB, upregulating intercellular adhesion molecule-1 (ICAM-1) and inducing MMP-9 expression. MMP-9 hydrolyzes ICAM-1 into s-ICAM-1, thereby enhancing tumor immune evasion.⁴¹⁴ In NSCLC, transmembrane mucin 3 A has been shown to stabilize EGFR. Its depletion inhibits the activation of the PI3K/AKT and MAPK cascades, resulting in reduced PD-L1 expression and attenuated immune evasion.⁴¹⁵

PI3K/AKT pathway and inhibitors

The PI3K/AKT signaling pathway, often found to be hyperactivated in diverse tumors, plays a pivotal role in regulating numerous biological processes, positioning it a crucial focus for the development of anticancer therapies. Intensive research efforts are focused on devising therapeutic strategies that specifically inhibit PI3K/AKT signaling. This paper provides a comprehensive overview of PI3K/AKT pathway inhibitors currently approved for clinical use or undergoing clinical trials (Table 4). Additionally, it explores the potential of combining these pathway inhibitors with other targeted agents to formulate personalized therapeutic approaches for various cancers (Fig. 8).

Table 4.

An overview of the inhibitors targeting the PI3K/AKT pathway

Type	Agents	Molecular Formula	Structure	Selectivity	Indications	Phase	Adverse events	Identifier	Ref.
Pan-PI3K inhibitors	Copanlisib	C23H28N8O4		PI3Kα and PI3Kδ	Recurrent indolent and aggressive non-Hodgkin’s lymphoma	I	Nausea and transient hyperglycemia	NCT00962611	419
					Recurrent indolent and aggressive non-Hodgkin’s lymphoma	II	Fatigue, diarrhea, and hyperglycemia	NCT01660451	418
					Relapsed indolent non-Hodgkin lymphoma	III	Diarrhea and hyperglycemia	NCT02367040	420
	Buparlisib/BKM120	C18H21F3N6O2		PI3Kα and PI3Kδ	Metastatic estrogen receptor-positive breast cancer	I	Fatigue, transaminases elevation, rash, and diarrhea	NCT01339442	422
					Triple-negative breast cancer	II	Fatigue, nausea, hyperglycemia, and anorexia	NCT01790932	423
					HER2-negative, advanced breast cancer	III	Elevated alanine aminotransferase, elevated aspartate aminotransferase, hyperglycemia, hypertension, and fatigue	NCT01633060	424
PI3K isoform-selective inhibitors	Inavolisib/GDC0077	C18H19F2N5O4		PI3Kα	HR-positive, HER2-negative breast cancer	III	Ongoing	NCT04191499	425
	GSK2636771	C22H22F3N3O3		PI3Kβ	Metastatic castration-resistant prostate cancer	I	Diarrhea, decreased appetite, fatigue, anemia, and hypocalcemia	NCT02215096	431
	AZD8186	C24H25F2N3O4		PI3Kβ	Prostate cancer, triple-negative breast cancer, and squamous non-small cell lung cancer	I	Constipation, diarrhea, nausea, vomiting, and fatigue	NCT01884285	433
					Metastatic or recurrent gastric cancer	Ib/II	Neutropenia, skin eruption, and stomatitis	NCT04001569	434
	Idelalisib	C22H18FN7O		PI3Kδ	Relapsed chronic lymphocytic leukemia	III	Pyrexia, fatigue, and diarrhea	NCT01539512	438
					Relapsed chronic lymphocytic leukemia	III	Pyrexia, fatigue, nausea, chills, and diarrhea	NCT01539512	437
	Leniolisib	C21H25F3N6O2		PI3Kδ	Activated phosphoinositide 3-kinase delta syndrome	III	Upper respiratory tract infection, headache, pyrexia, otitis externa, COVID-19, and increased weight	NCT02435173	442
	Eganelisib/IPI-549	C30H24N8O2		PI3Kγ	Advanced solid tumor	I/Ib	Pyrexia, rash, maculopapular rash, cytokine release syndrome, and infusion-related reaction	NCT02637531	447
	Duvelisib/IPI-145	C22H17ClN6O		PI3Kγ and PI3Kδ	Relapsed or refractory chronic lymphocytic leukemia and small lymphocytic lymphoma	III	Diarrhea, ALT/AST increased, neutropenia, fatigue, fever, and cough	NCT02004522	450
PI3K-mTOR dual inhibitors	Apitolisib /GDC-0980	C23H30N8O3S		PI3K and mTOR	Metastatic renal cell carcinoma	II	Rash, hyperglycemia, diarrhea, mucosal inflammation, nausea, and fatigue	NCT01442090	457
					Advanced solid malignancies, non-Hodgkin’s lymphoma, multiple myeloma with no standard treatments available	I	Hyperglycemia, rash, liver dysfunction, diarrhea, pneumonitis, and mucosal inflammation	NCT00854152	456
	Gedatolisib/PF-05212384/PKI-587	C32H41N9O4		PI3K, mTORC1 and mTORC2	Hormone receptor-positive, HER2-negative advanced breast cancer	Ib	Neutropenia, stomatitis, and rash	NCT02684032	462
					Hormone receptor-positive, HER2-negative advanced breast cancer	Ib	/	NCT06757634	463
AKT inhibitors	Capivasertib	C21H25ClN6O2		AKT1, AKT2, and AKT3	Metastatic, estrogen receptor-positive, HER2-negative breast cancer	II	Hypertension, diarrhea, and rash	NCT01992952	471
				AKT1, AKT2, and AKT3	ER+ metastatic breast cancer	III	Rash, hyperglycemia, and diarrhea	NCT04305496	472
	Uprosertib/GSK2141795	C18H16Cl2F2N4O2		AKT1, AKT2, and AKT3	Solid Tumors	I	Diarrhea, nausea, fatigue, vomiting, and decreased appetite	NCT00920257	475
	MK-2206	C25H21N5O		AKT1, AKT2, and AKT3	Recurrent/metastatic adenoid cystic carcinoma	II	Rash, fatigue, decreased lymphocyte count, and hyperglycemia	NCT01604772	478
					Advanced breast cancer	II	Fatigue, rash, vomiting, and nausea	NCT01277757	479
					Endometrial cancer	II	Rash, fatigue, nausea, and hyperglycemia	NCT01307631	480

Fig. 8.

PI3K/AKT signaling pathway and inhibitors. The PI3K/AKT pathway, which is crucial in regulating key biological processes, represents a major target for anticancer drug development. This figure outlines the inhibitors targeting the PI3K/AKT pathway, highlighting those currently in clinical use or under clinical investigation. PI3K phosphatidylinositol 3-kinase, AKT protein kinase B, mTOR, mammalian target of rapamycin. Figure created with BioRender (https://www.biorender.com)

Pan-PI3K inhibitors

Pan-PI3K inhibitors, designed to inhibit all four isoforms of class I PI3K, function as ATP-competitive inhibitors.⁴¹⁶ Representative agents such as copanlisib and buparlisib (BKM120) have demonstrated promising therapeutic potential in clinical applications. Copanlisib, a broad-spectrum inhibitor of class I PI3K, exhibits higher binding affinity for PI3Kα and PI3Kδ.⁴¹⁷ Clinically, copanlisib has demonstrated significant efficacy in treating recurrent indolent and aggressive non-Hodgkin’s lymphoma (NHL), as evidenced by results from phase I (NCT00962611) and phase II (NCT01660451) clinical trials.^418,419 Furthermore, phase III trial data (NCT02367040) indicate that combining copanlisib with rituximab significantly prolongs PFS in patients with NHL.⁴²⁰ However, its clinical utility is limited by the frequent occurrence of adverse events (AEs), including hypertension and hyperglycemia.

Buparlisib (BKM120), an orally bioavailable and highly potent inhibitor of class I PI3K, is currently being investigated for efficacy in solid tumors, such as BC and HNSCC. Buparlisib is also undergoing a global, multicenter phase III clinical trial (NCT04338399) in combination with paclitaxel for HNSCC, with approval from the Food and Drug Administration (FDA).⁴¹⁷ Preclinical studies demonstrated tumor regression in estrogen receptor-positive BC xenografts when combined with fulvestrant.⁴²¹ A phase I study reported preliminary clinical efficacy in advanced estrogen receptor-positive BC, while phase II trials linked buparlisib to prolonged stable disease in a subset of patients with triple-negative BC.^422,423 Phase III clinical evaluations have assessed the safety and efficacy of buparlisib in combination with fulvestrant in advanced BC cases.⁴²⁴ Despite its potential benefits, the widespread clinical application of buparlisib is constrained by the high incidence of adverse effects, including elevated alanine aminotransferase, hypertension, and hyperglycemia.

PI3K isoform-selective inhibitors

To mitigate toxic effects, specific ATP-competitive inhibitors have been developed for each PI3K isoform. Inavolisib (GDC0077), an orally administered inhibitor targeting PI3Kα, is currently under evaluation in a phase III clinical trial (NCT04191499) to assess its efficacy in combination with palbociclib and fulvestrant for HR-positive, HER2-negative BC harboring PIK3CA mutations.⁴²⁵ Alpelisib (BYL719), another potent oral PI3Kα inhibitor, specifically targets cancers with PIK3CA gene mutations.⁴²⁶ Recent studies have demonstrated synergistic effects when alpelisib is combined with other targeted agents, particularly in PIK3CA-mutated cancer cells across various malignancies.⁴²⁷ However, its clinical application is limited by AEs, including diarrhea, hyperglycemia, and skin rash.⁴²⁸ An emerging therapeutic agent, STX-478, functions as an allosteric inhibitor with selective affinity for mutant PI3Kα. Preclinical studies have shown that STX-478 effectively suppresses the growth of PIK3CA-mutant tumors in murine models. Unlike the FDA-approved alpelisib, STX-478 does not induce hyperglycemia or other metabolic disturbances, indicating a potentially safer profile.⁴²⁹

Selective inhibition of PI3Kβ offers the advantage of reducing both on-target and off-target toxicities commonly associated with pan-PI3K inhibitors.⁴³⁰ GSK2636771, a potent, orally bioavailable PI3Kβ inhibitor, competes with ATP and exhibits high specificity.⁴³⁰ In a phase I trial (NCT02215096), the combination of GSK2636771 with enzalutamide demonstrated acceptable safety and tolerability, with no novel or unexpected adverse effects.⁴³¹ Another selective PI3Kβ inhibitor, AZD8186, has demonstrated strong efficacy and specificity. Administered either as a monotherapy or in combination with other treatments, AZD8186 has shown favorable tolerability.⁴³² In an initial phase I study (NCT01884285), the optimal dosage was established and corroborated by pharmacokinetic and pharmacodynamic data.⁴³³ Furthermore, a phase Ib/II clinical trial identified the maximum tolerated dose of paclitaxel when combined with AZD8186, with long-term clinical benefits observed in patients with PIK3CB mutations.⁴³⁴ Additional studies targeting a more specific patient cohort are warranted to refine the therapeutic potential of AZD8186.

Numerous PI3Kδ inhibitors are presently under evaluation in early-phase clinical trials for hematological malignancies, with several having already gained regulatory approval.⁴³⁵ Idelalisib, an orally administered inhibitor with high specificity for PI3Kδ, has been developed primarily to target B-cell hematological cancers.^436,437 In a phase III clinical trial (NCT01539512), the combination of idelalisib and rituximab markedly enhanced PFS, response rate, and OS among patients with relapsed chronic lymphocytic leukemia (CLL) who demonstrated limited responsiveness to chemotherapy.⁴³⁸ Leniolisib, a newly developed small-molecule inhibitor also administered orally, specifically targets the PI3Kδ signaling pathway.⁴³⁹ It has demonstrated efficacy in addressing activated phosphoinositide 3-kinase delta syndrome (APDS), a genetic immune disorder caused by pathogenic mutations affecting the PI3Kδ heterodimer.^440,441 Long-term administration of leniolisib has shown favorable tolerance in patients with APDS, resulting in gradual improvement of characteristic disease manifestations.^442,443

PI3Kγ, predominantly expressed in white blood cells, is critically involved in controlling the migration of myeloid immune cells.⁴⁴⁴ It is increasingly recognized as a highly promising target for therapeutic intervention in inflammation, autoimmune diseases, and immuno-oncology.⁴⁴⁵ Eganelisib (IPI-549), an innovative, orally administered PI3Kγ inhibitor, has demonstrated antitumor efficacy both as a monotherapy and in combination with PD-1/PD-L1 inhibitors in preclinical models.⁴⁴⁶ The phase I/Ib clinical trial (NCT02637531), the first human study evaluating eganelisib as both a monotherapy and in combination with nivolumab in patients with advanced solid tumors, confirmed that the safety profile of both approaches was manageable.⁴⁴⁷

Duvelisib (IPI-145), a dual inhibitor targeting both PI3Kδ and PI3Kγ, received FDA approval in 2018 for the treatment of adult patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL).^448,449 In a phase III randomized clinical trial comparing duvelisib with the monoclonal antibody ofatumumab in patients with CLL/SLL, duvelisib demonstrated superior efficacy, leading to significant improvements in the overall response rate, PFS, and OS.⁴⁵⁰ Despite its clinical benefits, duvelisib use is associated with common AEs, including diarrhea, neutropenia, pyrexia, nausea, anemia, and cough.⁴⁵¹ Current clinical trials are focused on optimizing the therapeutic efficacy of duvelisib while minimizing its toxicity.

PI3K-mTOR dual inhibitors

The PI3K/AKT/mTOR signaling pathway is fundamental in inhibiting tumor cell apoptosis, promoting cell survival, regulating the cell cycle, and controlling tumor angiogenesis, invasion, and metastasis.⁴⁵² Its pivotal role in tumor development, prognosis, and therapeutic response makes it a critical target in cancer research.⁴⁵³ Inhibitors targeting the PI3K/AKT/mTOR axis exhibit anticancer activity by selectively inhibiting distinct pathway components.⁴⁵⁴

Apitolisib (GDC-0980), a dual PI3K/mTOR inhibitor, has demonstrated significant antitumor activity across multiple cancer models and is currently under clinical evaluation.⁴⁵⁵ In a phase I human trial (NCT00854152) involving patients with advanced solid tumors, apitolisib exhibited favorable drug absorption and antitumor efficacy.⁴⁵⁶ However, in a phase II study (NCT01442090) focusing on metastatic renal cell carcinoma, dual inhibition with apitolisib proved less effective than mTORC1 inhibition with everolimus, likely due to the occurrence of various on-target AEs stemming from comprehensive PI3K/mTOR pathway blockade.⁴⁵⁷

Gedatolisib (PF-05212384 or PKI-587) is a dual inhibitor that targets both the PI3K and mTOR signaling pathways.⁴⁵⁸ It inhibits all Class I PI3K isoforms and exerts effects on both mTOR complexes, namely, mTORC1 and mTORC2.⁴⁵⁹ Gedatolisib has shown antitumor activity in vitro and in vivo across multiple tumor types.⁴⁶⁰ Preliminary efficacy data from studies in various solid tumors indicate that it is associated with fewer adverse events compared to those reported for selective PI3K or mTOR inhibitors.^460,461 In a phase 1b clinical trial (NCT02684032) involving patients with hormone receptor-positive, HER2-negative advanced BC, the combination of gedatolisib and endocrine therapy exhibited superior safety and efficacy relative to standard treatment regimens reported in the literature.⁴⁶² Additionally, a phase 3 clinical trial (NCT06757634) has been initiated to assess the efficacy of gedatolisib in combination with a CDK4/6 inhibitor and fulvestrant as first-line therapy for patients with hormone receptor-positive, HER2-negative advanced BC.⁴⁶³

AKT inhibitors

AKT signaling dysregulation is closely linked to various diseases, particularly cancer, where hyperactivation of AKT contributes to enhanced cell survival, proliferation, and invasion.⁴⁶⁴ Multiple AKT inhibitors are in development and clinical testing as potential anticancer agents.⁴⁶⁵ These inhibitors are classified into three primary categories: ATP-competitive inhibitors, allosteric inhibitors, and covalent-allosteric inhibitors (CAAIs).⁴⁶⁶ Among them, selective ATP-competitive pan-AKT inhibitors, including capivasertib, ipatasertib (GDC0068), and uprosertib, have shown promising potential.^467,468

Capivasertib (AZD5363), an orally bioavailable, potent, and selective ATP-competitive pan-AKT kinase inhibitor, has demonstrated significant antitumor activity, particularly in BC cell lines.⁴⁶⁹ Preclinical studies have shown that capivasertib, in combination with endocrine therapy, enhances antitumor efficacy.⁴⁷⁰ In a phase II clinical trial (NCT01992952), capivasertib combined with fulvestrant significantly improved PFS and OS in postmenopausal women with hormone receptor-positive advanced BC.⁴⁷¹ Furthermore, a randomized, double-blind phase III trial (NCT04305496) demonstrated that adding capivasertib to fulvestrant significantly prolonged PFS in patients with hormone receptor-positive, HER2-negative advanced BC, reinforcing its therapeutic potential.⁴⁷²

Uprosertib (GSK2141795), another pan-AKT inhibitor that competes with ATP, has advanced to clinical trials.⁴⁷³ Uprosertib effectively binds to AKT kinase, inhibiting substrate phosphorylation and downstream signaling within the PI3K/AKT pathway, thereby suppressing tumor cell proliferation and inducing apoptosis.⁴⁷⁴ A phase I clinical trial in patients with solid tumors reported that uprosertib is both safe and well tolerated.⁴⁷⁵ However, a combination of trametinib and uprosertib did not yield substantial clinical efficacy in patients with wild-type melanoma.⁴⁷⁶ Despite this, preclinical data and multiple clinical studies suggest that uprosertib holds potential as an anticancer agent.

MK-2206, an orally administered and highly selective small molecule, is currently undergoing clinical evaluation for the treatment of solid tumors.⁴⁷⁷ Despite its high specificity, monotherapy with MK-2206 has not demonstrated favorable clinical responses in patients with various cancers, including BC, adenoid cystic carcinoma, and recurrent endometrial carcinoma.^478–480 However, preclinical studies have shown that combining MK-2206 with other targeted therapies can yield synergistic antitumor effects.⁴⁸¹ Notably, MK-2206 significantly enhanced the efficacy of mitoxantrone, SN-38, and topotecan in lung cancer cells exhibiting elevated levels of the ATP-binding cassette transporter G2.⁴⁸² These findings suggest that, despite limited standalone efficacy, MK-2206 retains potential clinical relevance when utilized in combination therapies.

Conclusion and perspectives

Dysregulation of the PI3K/AKT signaling pathway is a critical factor contributing to tumorigenesis. Approximately half of all human cancers harbor mutations in the PI3K/AKT pathway, making it the most commonly dysregulated signaling pathway in cancer biology.²⁰⁴ The core components of this pathway, including PI3K, AKT, mTOR, and PTEN, form an intricate network that integrates extracellular signals to regulate cellular responses. Aberrant expression or mutations in these key molecules, often driven by genetic alterations, gene amplifications, or epigenetic modifications, lead to persistent oncogenic signaling, thereby establishing this pathway as a central driver of tumorigenesis. PIK3CA mutations are common across a broad spectrum of human malignancies, whereas PIK3CG has been implicated in promoting immunosuppressive phenotypes within tumor-associated macrophages. AKT2 is primarily involved in insulin-responsive metabolic tissues, while AKT3 exhibits predominant expression in the brain. These molecular alterations critically influence tumor cell proliferation, survival, invasion, and metastasis.

Furthermore, the PI3K/AKT signaling network contributes to oncogenesis through extensive crosstalk with other key signaling pathways, such as NF-κB, MAPK, and JAK/STAT. The PI3K/AKT/mTORC1 axis, positioned downstream of Notch signaling, is instrumental in driving Th17 cell differentiation and is implicated in the pathophysiology of multiple autoimmune disorders. Additionally, the JAK2/STAT5 pathway directly interacts with the p58α regulatory subunit of PI3K, modulating breast cell survival and apoptosis. These interactions not only drive tumor growth and metastasis but also contribute to therapeutic resistance, complicating clinical management. Examining these interpathway interactions is essential for uncovering the complex mechanisms driving cancer progression and various disease states, thereby guiding the design of more integrated and effective treatment approaches.

The involvement of the PI3K/AKT signaling pathway in tumor initiation, progression, and immune evasion underscores its significance as a therapeutic target. The mechanisms by which the PI3K/AKT pathway contributes to tumorigenesis are multifaceted, encompassing metabolic reprogramming, regulation of programmed cell death, and angiogenesis. Although PI3K/AKT inhibitors have shown encouraging outcomes in preclinical and clinical investigations, issues including the development of drug resistance, reactivation of the signaling pathway, and systemic adverse effects underscore the necessity for more precise and effective therapeutic approaches.

Future research on the PI3K/AKT pathway may prioritize several key areas to improve therapeutic outcomes. First, further exploration of the functional dependencies between upstream and downstream components of the PI3K/AKT cascade can guide the development of more precise targeting strategies. Second, overcoming resistance mechanisms remains a major challenge. Combination therapies, such as simultaneous inhibition of PI3K/AKT and compensatory pathways (e.g., MEK or ERK inhibitors), may offer superior efficacy compared to monotherapy. Third, the development of isoform-specific PI3K inhibitors could reduce off-target effects while preserving antitumor activity. Advances in drug delivery systems, including nanoparticle-based formulations and antibody‒drug conjugates, hold promise for improving the bioavailability and tumor specificity of PI3K/AKT inhibitors while minimizing systemic toxicity.

Collectively, this review provides a comprehensive analysis of the core components of the PI3K/AKT pathway, emphasizing its interactions with other signaling cascades, elucidating its role in cancer progression, and summarizing the inhibitors currently in clinical use or under investigation. These inhibitors, especially when used in combination with other targeted therapies, hold significant promise for developing personalized cancer treatment. Despite notable advancements in targeting the PI3K/AKT pathway, resistance and toxicity remain major challenges. A deeper understanding of its role in oncogenesis is crucial for advancing both basic and translational research, ultimately guiding the development of more effective therapeutic interventions. In conclusion, although considerable progress has been made in elucidating the PI3K/AKT pathway in cancer, achieving durable clinical benefits will require multidisciplinary collaboration. Addressing these challenges may enable next-generation treatments targeting the PI3K/AKT pathway to fulfill their potential as transformative tools in oncology.

Author contributions

L.L. and D.Z. conceived, designed, and supervised the project. Q.S., J.L., and Q.C. conducted literature searches, drafted the manuscript, and prepared the figures. Y.F.Z. and Y.Q.Z. organized the tables. S.J. and X.Y. organized references. L.L. and D.Z. reviewed and edited the manuscript. All authors have read and approved the final version.

Competing interests

The authors declare no competing interests.