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Review
. 2016 Jun;4(12):237.
doi: 10.21037/atm.2016.06.07.

Resistant mechanisms to BRAF inhibitors in melanoma

José Luís Manzano  1 , Laura Layos  2 , Cristina Bugés  2 , María de Los Llanos Gil  2 , Laia Vila  2 , Eva Martínez-Balibrea  3 , Anna Martínez-Cardús  4
Affiliations
Review

Resistant mechanisms to BRAF inhibitors in melanoma

José Luís Manzano et al. Ann Transl Med. 2016 Jun.

Abstract

Patients with advanced melanoma have traditionally had very poor prognosis. However, since 2011 better understanding of the biology and epidemiology of this disease has revolutionized its treatment, with newer therapies becoming available. These newer therapies can be classified into immunotherapy and targeted therapy. The immunotherapy arsenal includes inhibitors of CTLA4, PD-1 and PDL-1, while targeted therapy focuses on BRAF and MEK. BRAF inhibitors (vemurafenib, dabrafenib) have shown benefit in terms of overall survival (OS) compared to chemotherapy, and their combination with MEK inhibitors has recently been shown to improve progression-free survival (PFS), compared with monotherapy with BRAF inhibitors. However, almost 20% of patients initially do not respond, due to intrinsic resistance to therapy and, of those who do, most eventually develop mechanisms of acquired resistance, including reactivation of the MAP kinase pathway, persistent activation of receptor tyrosine kinase (RTKS) receptor, activation of phosphatidyinositol-3OH kinase, overexpression of epidermal growth factor receptor (EGFR), and interactions with the tumor microenvironment. Herein we comment in detail on mechanisms of resistance to targeted therapy and discuss the strategies to overcome them.

Keywords: MAP kinase; Melanoma; biomarkers; resistance; targeted therapy.

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Conflict of interest statement

Conflicts of Interest: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
MAPK pathway. NSCLC, non-small-cell lung carcinoma; MAPK, mitogen-activated protein kinases.
Figure 2
Figure 2
Strategies to overcome resistance. CDK4, cyclin-dependent kinase 4.
See this image and copyright information in PMC

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