Resistance to selective BRAF inhibition can be mediated by modest upstream pathway activation
Menée in vitro, cette étude identifie un mécanisme de résistance à un traitement au vemurafenib chez les patients atteints d'un mélanome présentant une mutation BRAFV600E
A high percentage of patients with BRAFV600E-mutant melanomas respond to the selective RAF inhibitor vemurafenib (RG7204, PLX4032), but resistance eventually emerges. To better understand the mechanisms of resistance, we used chronic selection to establish BRAFV600E melanoma clones with acquired resistance to vemurafenib. These clones retained the V600E mutation and no second-site mutations were identified in the BRAF coding sequence. Further characterization demonstrated that vemurafenib was not able to inhibit ERK phosphorylation, suggesting pathway re-activation. Importantly, resistance also correlated with increased levels of RAS-GTP, and sequencing of RAS genes revealed a rare activating mutation in KRAS, resulting in a K117N change in the KRAS protein. Elevated levels of CRAF and phosphorylated AKT were also observed. In addition, combination treatment with vemurafenib and either a MEK inhibitor or an AKT inhibitor synergistically inhibited proliferation of resistant cells. These findings suggest that resistance to BRAFV600E inhibition could occur through several mechanisms, including elevated RAS-GTP levels and increased levels of AKT phosphorylation. Together, our data implicate reactivation of the RAS/RAF pathway by upstream signaling activation as a key mechanism of acquired resistance to vemurafenib, in support of clinical studies in which combination therapy with other targeted agents are being strategized to combat resistance.