The Role of the Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Cancer

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Sajedeh Lotfaliansaremi Michael Sabio Stephen Comwell Peter Tolias

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.

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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://journals.ke-i.org/mra/article/view/2086>. Date accessed: 03 june 2020. doi: https://doi.org/10.18103/mra.v8i4.2086.
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