The Role of the Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Cancer
Main Article Content
Abstract
The Ras-ERK mitogen-activated protein kinase (MAPK) pathway is hyperactive in >30% of all human cancers, prompting the development of RAS, RAF, MEK, and ERK inhibitors. The identification of intracellular signaling cascades, which promote the growth and survival of cancer cells, is critical for developing targeted cancer therapeutics aimed at blocking these signals. Currently, there are various FDA-approved drugs to inhibit RAF and MEK mutations for cancer treatment, but patients rapidly develop resistance to these drugs within several months, necessitating the need to develop new drugs against other targets in the MAPK pathway. Developing RAS inhibitors has been challenging due to the high affinity of RAS for its natural ligands (GDP and GTP) and the lack of a druggable binding cavity. As an alternative to targeting RAS, ERK inhibitors, which have also been shown to work on RAF/MEK-resistant cell lines, can block the activation of ERK and act as an effective cancer treatment, causing tumor regression. However, to maximize therapeutic effectiveness, it seems unlikely that any monotherapy would be particularly useful. Future treatment strategies should be designed on a patient-by-patient basis to ensure the most rapid reduction in tumor growth and the minimization of off-target effects by using a combination of two (or more) inhibitors within this MAPK pathway that lead to tumor regression and positive patient outcomes.
Keywords:
mitogen-activated protein kinases, MAPKs, cancer, signaling, feedback regulation, activators, amplifiers, negative feedback, therapeutic targets, RAS, RAF, BRAF, BRAFV600E, MEK, ERK, RTK, NF1
Article Details
How to Cite
LOTFALIANSAREMI, Sajedeh et al.
The Role of the Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Cancer.
Medical Research Archives, [S.l.], v. 8, n. 4, apr. 2020.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2086>. Date accessed: 26 dec. 2024.
doi: https://doi.org/10.18103/mra.v8i4.2086.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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6. McCubrey JA, Milella M, Tafuri A, et al. Targeting the Raf/MEK/ERK pathway with small-molecule inhibitors. Curr Opin Investig Drugs. 2008;9(6):614–630.
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8. Ray LB, Sturgill TW. Characterization of insulin-stimulated microtubule-associated protein kinase. Rapid isolation and stabilization of a novel serine/threonine kinase from 3T3-L1 cells. J Biol Chem. 1988;263(25):12721–12727.
9. Ahn NG, Krebs EG. Evidence for an epidermal growth factor-stimulated protein kinase cascade in Swiss 3T3 cells. Activation of serine peptide kinase activity by myelin basic protein kinases in vitro. J Biol Chem. 1990;265(20):11495–11501.
10. Merchant M, Moffat J, Schaefer G, et al. Combined MEK and ERK inhibition overcomes therapy-mediated pathway reactivation in RAS mutant tumors. PLoS One. 2017;12(10):e0185862. doi:10.1371/journal.pone.0185862. Corrections in PLoS One. 2018;13(1):e0192059. doi:10.1371/journal.pone.0192059.
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12. Braicu C, Buse M, Busuioc C, et al. A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer. Cancers (Basel). 2019;11(10):pii-E1618. doi:10.3390/cancers11101618.
13. Yaeger R, Corcoran RB. Targeting Alterations in the RAF–MEK Pathway. Cancer Discov. 2019;9(3):329–341. doi:10.1158/2159-8290.CD-18-1321.
14. Li L, Feng J, Wu T, et al. Inhibitors of KRAS G12C. World Intellectual Property Organization. 2015; Patent application WO 2015/054572 A1.
15. Milburn MV, Tong L, deVos AM, et al. Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science. 1990;247(4945):939–945. doi:10.1126/science.2406906.
16. McCain J. The MAPK (ERK) pathway: investigational combinations for the treatment of BRAF-mutated metastatic melanoma. P T. 2013;38(2):96–108.
17. Ryan MB, Corcoran RB. Therapeutic strategies to target RAS-mutant cancers. Nat Rev Clin Oncol. 2018;15(11):709–720. doi:10.1038/s41571-018-0105-0.
18. Hayes TK, Der CJ. Mutant and wild-type Ras: co-conspirators in cancer. Cancer Discov. 2013;3(1):24–26. doi:10.1158/2159-8290.CD-12-0521.
19. Jarvis, LM. Have drug hunters finally cracked KRas? C&EN. 2016;94(23):28–33.
20. Yaeger R, Yao Z, Hyman DM, et al. Mechanisms of acquired resistance to BRAF V600E inhibition in colon cancers converge on RAF dimerization and are sensitive to its inhibition. Cancer Res. 2017;77(23):6513–6523. doi:10.1158/0008-5472.CAN-17-0768.
21. Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170(1):17–33. doi:10.1016/j.cell.2017.06.009.
22. McDonald ER 3rd, de Weck A, Schlabach MR, et al.; Project DRIVE: a compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi screening. Cell. 2017;170(3):577–592.e10. doi:10.1016/j.cell.2017.07.005.
23. Yuen JS, Sim MY, Sim HG, et al. Combination of the ERK inhibitor AZD6244 and low-dose sorafenib in a xenograft model of human renal cell carcinoma. Int J Oncol. 2012;41(2):712–720. doi:10.3892/ijo.2012.1494.
24. Karoulia Z, Gavathiotis E, Poulikakos PI. New perspectives for targeting RAF kinase in human cancer. Nat Rev Cancer. 2017;17(11):676–691. doi:10.1038/nrc.2017.79.
25. Ni D, Li X, He X, Zhang H, Zhang J, Lu S. Drugging K-RasG12C through covalent inhibitors: Mission possible? Pharmacol Ther. 2019;202:1–17. doi:10.1016/j.pharmthera.2019.06.007.
26. Ghosh AK, Samanta I, Mondal A, Liu WR. Covalent inhibition in drug discovery. ChemMedChem. 2019;14(9):889–906. doi:10.1002/cmdc.201900107.
27. Ledford H. Cancer: the Ras renaissance. Nature. 2015;520(7547):278–280. doi:10.1038/520278a.
28. Lim SM, Westover KD, Ficarro SB, et al. Therapeutic targeting of oncogenic K-Ras by a covalent catalytic site inhibitor. Angew Chem Int Ed Engl. 2014;53(1):199–204. doi:10.1002/anie.201307387.
29. Nagasaka M, Li Y, Sukari A, Ou SI, Al-Hallak MN, Azmi AS. KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne? Cancer Treat Rev. 2020;84:101974. doi:10.1016/j.ctrv.2020.101974.
30. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–954. doi:10.1038/nature00766.
31. Huleihel M, Goldsborough M, Cleveland J, Gunnell M, Bonner T, Rapp UR. Characterization of murine A-raf, a new oncogene related to the v-raf oncogene. Mol Cell Biol. 1986;6(7):2655–2662. doi:10.1128/mcb.6.7.2655.
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