Melanoma: three ways around BRAF inhibition

Abstract

Independent research teams have identified three mechanisms by which melanoma can develop resistance to BRAF inhibitors, 1,2 a promising class of therapeutics that include late-stage clinical com-pounds from Plexxikon Inc. and GlaxoSmithKline plc. The findings suggest that BRAF inhibitors will need to be combined with other types of drugs, although future studies will have to determine the relative frequency of each mechanism. About 60% of melanomas express an activating mutation in the ser-ine/threonine kinase BRAF that enables tumor cell growth and pro-liferation. The most advanced inhibitor of mutant BRAF is PLX4032 (R7204; RG7204) from Plexxikon and Roche. The compound is in Phase III testing. Phase II data showed that some patients whose melanoma initially responded to the compound later developed resistance. 3,4 To identify the mechanisms underlying that resistance, a U.S.-Australian team and a U.S.-Swiss team each conducted in vitro testing in BRAF inhibitor–resistant human melanoma cell lines and tumor samples from patients treated with PLX4032. Collectively, the two teams found that BRAF inhibition induced one of three prosurvival mechanisms in melanoma (see Figure 1, " Pathways of acquired resistance in melanoma "). The U.S.-Australian team found that expression of mutant NRAS (neuroblastoma Ras viral (v-Ras) oncogene) activated the signaling of MAP kinase kinase 1 (MAP2K1; MEK1) and MAP2K2 (MEK2) in some resistant tumors. The group also found that overexpression of platelet derived growth factor B (PDGFB; PDGF2) enabled tumor cell survival via an undetermined pathway in a different subset of resistant tumors.