A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer
Abstract
:1. Oncogene Cooperation in a Game of Multistep Carcinogenesis
2. Mutant p53 Gain-of-Function
3. CMYC and MYC Family of Proteins
4. KRAS and RAS Family of Proteins
5. PI3K and BRAF
6. Telomerase
7. Cellular Proteasome Machinery
8. HSP Molecular Chaperones
9. NF-κB
10. AP-1—FOS/JUN
11. β-catenin and the WNT Pathway
12. YAP/TAZ
13. Non-coding RNAs (Micro RNAs and Long Non-codong RNAs)
14. Exploitation of the Oncogene Cooperation in Clinics
15. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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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] |
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Grzes, M.; Oron, M.; Staszczak, Z.; Jaiswar, A.; Nowak-Niezgoda, M.; Walerych, D. A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer. Cancers 2020, 12, 1532. https://doi.org/10.3390/cancers12061532
Grzes M, Oron M, Staszczak Z, Jaiswar A, Nowak-Niezgoda M, Walerych D. A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer. Cancers. 2020; 12(6):1532. https://doi.org/10.3390/cancers12061532
Chicago/Turabian StyleGrzes, Maria, Magdalena Oron, Zuzanna Staszczak, Akanksha Jaiswar, Magdalena Nowak-Niezgoda, and Dawid Walerych. 2020. "A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer" Cancers 12, no. 6: 1532. https://doi.org/10.3390/cancers12061532