Table 1.

Upstream and downstream interplays of the universal oncogenic drivers described in the text along with the current and proposed therapeutic solutions.

Oncogenic Driver Protein Name	Frequency/Mode of Activation in Multi-Neoplasia Studies	Upstream and Partner Oncogenic Factors Crosstalk	Downstream Oncogenic Process/Pathway/Target Examples	Direct Clinical Options in Neoplasia	Examples of Proposed/Tested Combinations with Other Targeted Therapies	Refs.
Mutant p53	42–43% mutated (of which >70% are missense—potential gain of function driver mutations)	Molecular chaperones, transcription co-factors: ETS2, SREBP1/2, NRF2, NFY, NF-κB, STAT3, YAP/TAZ; other partners: MRE11, Drosha/Dicer, DAB2IP	Genomic stability, steroid synthesis, epigenetic alterations, nucleotide synthesis, proteostasis, miRNA maturation, cell cycle/proliferation, migration/invasion	APR-246 (PRIMA-1 MET) in clinical trials	HSP90 inhibitors, HDAC inhibitors, proteasome inhibitors, statins	[11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,130,132,162,163,176,194,196,231,232,233, 240,253,254]
CMYC	5–20% mutated (of which >70% are amplifications), estimated hyperactive in majority of neoplasias	Transcription co-factor MAX, Pathways: Hedgehog, WNT, NOTCH, KRAS, PI3K, JAK-STAT3, MAPK-HNRP and mTORC1-S6K1, ncRNAs	Cell cycle (cyclins), metabolism (LDHA), apoptosis (BCL-XL), RNA splicing (PRMT5), immortalization (hTERT)	No direct inhibitors in clinics for neoplasia treatment (only preclinical).	CMYC-MAX complex inhibitors, inhibitors of RAS/PI3K/BRAF-related signaling	[7,8,9,10,29,33,34,49, 55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,91,92,106,107,109,135,136,150,151,164,165,199,220,234,245,246,247,252]
KRAS	7–17% mutated (up to 90% of which are missense driver mutations)	Receptor kinases (e.g. EGFR, CMET, HER2) (mutations in RAS provide independence)	metabolism, angiogenesis, proliferation, diffe-rentiation, migration via PI3K-AKT-mTOR, RAF-MEK-ERK, TKB1- NF-κB pathways, CMYC, hTERT	Small molecule KRAS G12C inhibitors (AMG 510, MRTX849) in clinical trials	Inhibitors of up- or downstream modulators (receptor kinases, PI3K, MEK, mTOR, BRAF etc.)	[4,5,6,7,47,48,50,64, 65,71,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,162,171,172,179,181,195,197,219, 226,234,241,242,243,260]
PI3 kinase	10–18% mutated (>80% of which are missense driver mutations)	Receptor tyrosine kinases, RTK, GRB2, KRAS (mutations in PIK gene provide independence), molecular chaperones	Proliferation/metabolism via AKT-mTOR pathway	Idelalisib (in standard protocol); multiple inhibitors tested in clinical trials	Downstream pathway components targeting (mTOR inhibitors), parallel pathway targeting (BRAF pathway inhibitors)	[64,85,96,97,100,173, 226]
BRAF	1.5–7% (majority are missense driver mutations)	Receptor tyrosine kinases, KRAS (mutations in BRAF gene provide independence), molecular chaperones	Proliferation/metabolism via MEK-ERK pathway	BRAF mutant inhibitors in standard protocols (e.g., vemurafenib and dabrafenib)	Upstream and downstream pathway components (EGFR or MEK inhibitors), parallel pathways (PI3K inhibitors), HSP90 inhibitors, immuno-therapy, angiogenic modulators	[98,99,101,258,264,265, 267]
Telomerase (hTERT)	15% mutated (>80% of which are promoter activating mutations); estimated active in 90% of neoplasias	CMYC, FoxM1, ETS family, SYMD3, molecular chaperones	Telomere-mediated cellular immortality; telomere independent activities: β-catenin/WNT, CMYC, mitochondrial apoptosis inhibition	Small molecule inhibitors (e.g., GRN163L) and peptide-based vaccines (e.g., GV1001) in clinical trials	Tested in combinations with immunotherapies and chemotherapy	[4,5,6,7,51,66,86,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117, 148,165,201]
Proteasome machinery (26S, 20S proteasome, immunoproteasome)	Mutations rare, estimated hyperactive and addictive in most neoplasias	NRF1, NRF2, STAT3, NFY, mutant p53, ubiquitin ligases and associated enzymes	Protein homeostasis (including inhibition of tumor suppressive pathways); activation of NF-κB and WNT pathways, molecular chaperones	Inhibitors in standard protocols (Bortezomib, Carfilzomib), other inhibitors tested	Autophagy inhibitors, HDACs inhibitors, oncogenic kinases inhibitors, NRF1/NRF2 inhibitors, mutant p53 targeting	[38,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,159,160,262,263]
Molecular chaperones (HSP90 and HSP70 families and co-chaperones)	Mutations rare, estimated addictive in most neoplasias	HSF1, HOP, small HSPs and HSP40 family co-chaperones	Client proteins including: mutant p53, kinases (e.g., SRC, CMET, EGFR, HER2), hTERT, CMYC, proteasome machinery activity	Multiple HSP90 and HSP70 inhibitors in clinical trials	HSF-1 inhibitors, co-chaperone inhibitors (e.g., targeting HOP or HSP40 proteins), oncogenic kinase inhibitors	[22,24,25,124,142,157, 263,264]
NF-κB	Overexpressed in 1–12% neoplasias; activatory kinases overexpressed in 1.5–18% neoplasias	EGFR, RAS family, HER2, proteasome	CMYC, cyclins, cytokines influencing cell proliferation, survival, angiogenesis and metastasis	No direct inhibitors in clinics for neoplasia treatment (only preclinical)	Targeting of upstream pathways – proteasome, RAS/PI3K/BRAF-related pathways, receptor kinases (e.g., HER2 or EGFR)	[40,120,133,158,159,160,161,162,163,164,165,175]
AP-1 (primarily FOS-JUN family protein dimers)	Mutations in FOS and JUN genes below 1%; estimated addictive in a large proportion of neoplasias	RAS family, MEKs, MAPKs, NF-κB, mutant p53, YAP/TAZ, ETS family	Invasiveness (MMP genes), proliferation (EGF pathway genes), oncogenic miRNAs (e.g., miR-21).	No direct inhibitors in clinics for neoplasia treatment (only preclinical)	Preclinical repositioning of AP-1 inhibitors tested in other diseases (e.g., T-5224 or SR 11302), rarely combined with other therapeutics	[166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183]
β-catenin and WNT pathway	7–10% inactivating mutations in APC, <3% mutations in other WNT pathway proteins, estimated hyperactive especially in tumor-generating neoplasias	Receptor-ligand pairs: FZD-WNT, LGR/R-spondin, EGFR-EGF, EG2-PGE2; β-catenin destruction complex and nuclear co-factors: LEF, TCF, PAF, YAP1, hTERT	Cell proliferation and tumor growth via CMYC, CJUN, hTERT, targets of AP-1 or NFAT (in non-canonical signaling)	Repositioning of approved anti-WNT drugs to cancer treatment (e.g., Niclosamide, Sulindac), other inhibitors in trials	Combination with PI3K/AKT/mTOR inhibitors, multikinase inhibitors (e.g., sorafenib) and chemotherapeutics	[113,134,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209]
YAP and TAZ	1–1.5% mutated YAP1 (up to 40% amplifications); estimated hyperactive in most tumor-generating neoplasias	Rho GTPases and cytoskeleton stiffness, GNAQ and GNA11, mevalonate pathway, β-catenin, CMYC, mutant p53, BRD4, AP-1, TEADs	Inhibition of apoptosis (e.g., BIRC5 and BCL2L1), tissue growth/stiffness/cell proliferation (e.g., AREG, CTGF)	No direct inhibitors in clinics for neoplasia treatment (only preclinical)	BET inhibitors, statins	[32,133,180,210,211,212,213,214,215,216,217,218,219,220,221,222,223]
non-coding RNAs (micro RNAs and long non-coding RNAs)	Copy number alterations, SNPs and promoter mutations so far found in single studies	miRNA maturation factors (Dicer, Drosha, DGCR8, KSRP) and their regulators e.g., mutant p53, proteasome; upregulators of specific ncRNA transcription or stability—e.g., CMYC	Cell proliferation (e.g. via RAS and PI3K-AKT pathway, CMYC, MCL1), tumor growth (e.g., via WNT pathway), cancer cell metabolic support (e.g., via STAT1, ATG7, Beclin1), chromatin reprogramming	Inhibition of oncogenic miRNAs (e.g., miR-155 by MRG-106) or targeting cells with overexpression of H19 lncRNA (by BC-819) in clinical trials	Next to none tested so far; suggested are downstream pathways and upstream regulators, such as CMYC pathway or mutant p53-proteasome-KSRP axis	[38,44,67,68,69,224,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257]