The New England Journal of Medicine, 2012, Vol.367(24), pp.2316-2321
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. A man with undiagnosed chronic myelomonocytic leukemia began treatment with vemurafenib for BRAF-mutant metastatic melanoma. His white-cell count soared and then dropped when the drug was withdrawn. The leukemia cells contained an RAS mutation that became more active with RAF inhibition. Approximately 50% of patients with metastatic melanoma harbor a somatic V600E mutation — or, less frequently, a V600K mutation — in the BRAF kinase.1–4 These activating mutations drive increased ERK signaling, promoting the proliferation and survival of melanoma cells.5 Selective RAF inhibitors, such as vemurafenib and dabrafenib, inhibit ERK signaling and arrest growth in tumors with BRAF V600E or BRAF V600K mutations.3,6–8 Treatment with vemurafenib or dabrafenib induces tumor regression in more than half of patients with BRAF V600E–mutant metastatic melanoma. Both drugs also improve the rate of progression-free survival, as compared with dacarbazine.7,9–11 Vemurafenib . . .