Resistance to Raf inhibition in cancer

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.

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.