Progression of RAS-Mutant Leukemia during RAF Inhibitor Treatment

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Abstract
Vemurafenib, a selective RAF inhibitor, extends survival among patients with BRAF V600E–mutant melanoma. Vemurafenib inhibits ERK signaling in BRAF V600E–mutant cells but activates ERK signaling in BRAF wild-type cells. This paradoxical activation of ERK signaling is the mechanistic basis for the development of RAS-mutant 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.