Abstract

Sum m a r yVemurafenib, a selective RAF inhibitor, extends survival among patients with BRAF V600E-mutant melanoma.Vemurafenib inhibits ERK signaling in BRAF V600Emutant cells but activates ERK signaling in BRAF wild-type cells.This paradoxical activation of ERK signaling is the mechanistic basis for the development of RASmutant squamous-cell skin cancers in patients treated with RAF inhibitors.We report the accelerated growth of a previously unsuspected RAS-mutant leukemia in a patient with melanoma who was receiving vemurafenib.Exposure to vemurafenib induced hyperactivation of ERK signaling and proliferation of the leukemic cell population, an effect that was reversed on drug withdrawal.