Mutational activation of BRAF is the most prevalent genetic alteration in melanoma, with ≥ 50% of tumors expressing the BRAF(V600E) oncoprotein. Vemurafenib (Zelboraf) produces tumor regression and improved survival in patients with late-stage BRAF-mutated melanoma. However, most patients relapse with drug-resistant disease, suggesting that understanding and preventing resistance may lead to improved therapy.
In a recent study, Das Thakur and colleagues from Novartis Institutes for Biomedical Research in Emeryville, California, and Cambridge, Massachusetts; University of California, San Francisco; and University Hospital Zurich, Switzerland found that modulation of vemurafenib dosing in primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration could forestall vemurafenib resistance.
In one of the models, the investigators found that resistant tumors show continued dependency on BRAF(V600E)→MEK→ERK signaling as a result of elevated BRAF(V600E) expression (eg, rather than additional mutations). They then showed that vemurafenib-resistant melanomas became drug dependent for their continued proliferation, with cessation of drug administration leading to regression of established drug-resistant tumors within 10 days, followed by regrowth. They further showed that a discontinuous dosing strategy forestalled the onset of lethal drug-resistant disease.
The investigators concluded, “These data highlight the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. Such observations may contribute to sustaining the durability of the vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.”
Das Thakur M, et al: Nature. January 9, 2013 (early release online).