Table 3.

Main non-receptor kinases related to apoptosis inhibition in human cancer.

	Kinase	Overview	Significance in Cancer
PI3K/AKT/mTOR pathway	PI3K	Transmits extracellular signals from receptor tyrosine kinases within the cell by catalyzing the production of PIP3, a phospholipid which triggers the activation of downstream signaling components such as AKT [97].	Directly implicated in the promotion of cell growth and survival [97]. Aberrant PI3K is implicated in 30%–50% of human cancers [97], PD-L1 overexpression and resistance to immunotherapy [4].
	AKT (AKT1, AKT2, AKT3)	One of the PI3K mediators, AKT phosphorylates and regulates the function of cellular proteins involved in metabolism, survival/apoptosis, differentiation and proliferation [98].	The most commonly dysregulated or mutated pathway in human cancer [99] contributes to PD-L1 overexpression [100] and apoptosis inhibition [101,102].
	mTOR (mTOR1, mTOR2)	Responsible for the phosphorylation and activation of AKT, mTOR is involved in the regulation of at least 800 different proteins [43].	Considered a master regulator of mammalian cell survival, proliferation and metabolism [103], aberrant expression or functioning of both mTOR1 and mTOR2 is found in up to 80% of human cancers [103,104] affecting tumor microenvironment and effector function [105].
MAPKs Pathway	RAS/RAF/MEK/ERK	Active ERKs phosphorylate different cytoplasmic and nuclear targets such as kinases, phosphatases, transcription factors and cytoskeletal proteins [106].	ERK pathway is deregulated in approximately one-third of all human cancers [106], with inhibitory effects on T-cell recruitment and function [4]. Activating mutations in RAS-RAF are frequent and key points to this pathway deregulation [106].
	JNKs	As master kinases, JNKs phosphorylate different transcription factors [106] and regulate physiological processes including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival and death. In response to cellular stress, JNK binds to and phosphorylates tumor-suppressor p53 [106].	Persistent activation of JNK is involved in cancer development and progression [107].
	MAPK14 (p38)	p38 is activated by environmental stresses and inflammatory cytokines and phosphorylates different transcription factors [106]. p38 is required for TNFα and interleukin-1 expression during inflammatory responses [106].	A decrease in p38 activity plays an important role in cancer since it has a tumor-suppressive effect and plays a key role in the regulation of apoptosis, cell cycle progression, growth and differentiation [106]. Different chemotherapeutic agents require p38 activity for the induction of apoptosis [106]. Accordingly, the aberrant expression of MAPK has inhibitory effects on T-cell recruitment and function [4].
PTEN	PTEN	This dual-specificity protein and lipid phosphatase blocks PI3K signaling by inhibiting PI3P-dependent processes such as AKT membrane recruitment and activation [108], which results in the inhibition of cell proliferation and survival [43].	PTEN is one of the most frequently disrupted tumor suppressors in human cancer [43] whose loss has been related to resistance to anti-PD-1 blockade therapy [109].
JAK/STAT	JAK/STAT	The JAK/STAT signaling pathway is the principal signaling mechanism for different cytokines and growth factors, being involved in processes such as immunity, cell proliferation, differentiation, migration and apoptosis [25].	Mutations in JAK1, JAK2 genes are associated with primary and acquired resistance to PD-1 blockade therapy [110].
	STK11/LKB1	This tumor suppressor serine/threonine kinase controls the activity of AMPK family members, playing a key role in cell metabolism, cell polarity, apoptosis or DNA damage response [111]	In advanced non-squamous lung cancer, somatic STK11/LKB1 mutations confer resistance to PD-L1 checkpoint inhibitors as monotherapy or in combination [112].

PI3K: phosphatidylinositol-3-kinase; PI3P: phosphatidylinositol (3,4,5)-triphosphate; AKT: protein kinase B; mTOR: mammalian target of rapamycin; MAPKs: mitogen-activated protein kinases; RAF: rapidly accelerated fibrosarcoma; ERK: extracellular-signal regulated kinase; MEK: MAPK/ERK kinase; JNK: c-Jun N-terminal kinase; TNF: tumor necrosis factor; PTEN: phosphatase and tensin homologue deleted on chromosome 10. AMPK: AMP-activated protein kinase. STK11/LKB1: serine/threonine kinase 11/liver kinase B1.