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Review
. 2018 Oct 17:11:7095-7107.
doi: 10.2147/OTT.S182721. eCollection 2018.

Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma

Sunilkumar Kakadia  1 , Naveen Yarlagadda  1 , Ramez Awad  2 , Madappa Kundranda  3 , Jiaxin Niu  3 , Boris Naraev  3 , Lida Mina  3 , Tomislav Dragovich  3 , Mark Gimbel  3 , Fade Mahmoud  3
Affiliations
Review

Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma

Sunilkumar Kakadia et al. Onco Targets Ther. .

Abstract

Approximately 50% of melanomas harbor an activating BRAF mutation. Combined BRAF and MEK inhibitors such as dabrafenib and trametinib, vemurafenib and cobimetinib, and encorafenib and binimetinib are US Food and Drug Administration (FDA)-approved to treat patients with BRAF V600-mutated advanced melanoma. Both genetic and epigenetic alterations play a major role in resistance to BRAF inhibitors by reactivation of the MAPK and/or the PI3K-Akt pathways. The role of BRAF inhibitors in modulating the immunomicroenvironment and perhaps enhancing the efficacy of checkpoint inhibitors is gaining interest. This article provides a comprehensive review of mechanisms of resistance to BRAF and MEK inhibitors in melanoma and summarizes landmark trials that led to the FDA approval of BRAF and MEK inhibitors in metastatic melanoma.

Keywords: BRAF inhibitor; MEK inhibitor; malignant melanoma; resistance; targeted therapy.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
MAPK–PI3K–Akt pathway and BRAFV600 mutation in melanoma. Notes: MAPK pathway in normal cells (left), where growth factors bound to RTK result in phosphorylation of Ras kinase, which further activates downstream kinases (Raf–MEK–ERK and PI3K–Akt–mTOR) and regulates the activities of several transcription factors responsible for cell growth, survival, and proliferation. BRAFV600 mutations in melanoma lead to constitutive activation of the MAPK pathway, which leads to uncontrolled cell survival, growth, and proliferation in malignant melanoma (right) that might be reversed, at least temporarily, by treatment with BRAF inhibitors.
Figure 2
Figure 2
Genetic and epigenetic causes of resistance to BRAF inhibitors in melanoma. Notes: Mechanisms of resistance to BRAF inhibitors in metastatic melanoma. Genetic changes leading to resistance to BRAF inhibitors include NRAS mutation, BRAF amplification, MEK mutations, NF1 mutations Akt amplification (genetic or epigenetic), and loss of PTEN (genetic or epigenetic), while epigenetic changes include Akt amplification, loss of PTEN, overexpression of HGF, RTK, PDGFRβ, and IGF1R.
See this image and copyright information in PMC

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