BRAF Inhibition Can Induce Noncutaneous RAS-Mutant Cancers

Targeted inhibition of BRAF with small-molecule agents such as vemurafenib and dabrafenib blocks ERK signaling and induces tumor regression in over half of patients with BRAF-mutant metastatic melanoma, leading to prolonged overall survival. However, BRAF inhibitors paradoxically stimulate ERK signaling in BRAF–wild-type cells in a RAS-dependent manner, which therefore promotes the proliferation of preexisting cells harboring RAS mutations and leads to an increased incidence of secondary RAS-mutant cutaneous neoplasms such as keratoacanthomas and squamous cell carcinomas in treated patients. Callahan and colleagues present the case of a patient with metastatic BRAF-mutant melanoma who was treated with vemurafenib and developed chronic myelomonocytic leukemia (CMML) that partially resolved whenever the drug was discontinued. An activating NRAS^G12R mutation was identified in the patient's leukemic cells, suggesting that paradoxical ERK activation also could lead to the preferential expansion of preexisting NRAS-mutant CMML cells. Indeed, ERK phosphorylation was selectively elevated in NRAS-mutant leukemic monocytes obtained when the patient was taking vemurafenib compared with monocytes obtained when he was not. Because combining MEK inhibition with BRAF inhibition has been shown to suppress paradoxical ERK activation and decrease the incidence of secondary skin tumors, the authors compared the effects of a BRAF inhibitor on proliferation and ERK signaling in NRAS-mutant leukemic cells, alone or in combination with a MEK inhibitor. Consistent with the findings in cutaneous tumors, single-agent BRAF inhibition increased colony formation and stimulated ERK signaling, whereas the addition of a MEK inhibitor significantly reduced proliferation and ERK activation. This case report provides evidence that RAS-mutant hematologic malignancies can also arise due to BRAF inhibitor–induced paradoxical ERK activation, a finding that should be considered in monitoring of patients treated with this class of drugs.

Callahan MK, Rampal R, Harding JJ, Klimek VM, Chung YR, Merghoub T, et al. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N Engl J Med 2012;367:2316–21.

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