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Review
. 2014 Mar:11:27-32.
doi: 10.1016/j.ddtec.2013.12.004.

Resistance to Raf inhibition in cancer

H Eirik Haarberg, Keiran S M Smalley
Review

Resistance to Raf inhibition in cancer

H Eirik Haarberg et al. Drug Discov Today Technol. 2014 Mar.

Abstract

The use of small molecule BRAF inhibitors has revolutionized the treatment of advanced melanoma. Despite this, resistance is commonplace and associated with a median progression-free survival of >5 months. Major resistance mechanisms include reactivation of the MAPK pathway and increased PI3K/AKT signaling. Here we review some of the combination therapeutic strategies currently undergoing evaluation for the management of acquired drug resistance in melanoma.

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Conflict of interest statement

Conflict of interest: The author(s) have no conflict of interest to declare.

Figures

Figure 1
Figure 1
Outline of the major signaling pathways in melanoma and potential mechanisms of acquired/intrinsic BRAF inhibitor resistance. Reactivation of MAPK signaling is a common feature of acquired RAF inhibitor resistance and can be mediated through increased RTK signaling, CRAF/BRAF amplification, increased Cot expression and the dimerization of BRAF splice-mutants as well as via activating mutations in NRAS and MEK1/2. Increased PI3K/AKT signaling, resulting from RTK signaling and genetic lesions in PTEN and NF1 can also contribute to BRAF inhibitor resistance.
See this image and copyright information in PMC

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