Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with ≥50% of tumours expressing the BRAF(V600E) oncoprotein1,2. Moreover, the marked tumour regression and improved survival of late-stage BRAF-mutated melanoma patients in response to treatment with vemurafenib demonstrates the essential role of oncogenic BRAF in melanoma maintenance3,4. However, as most patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is critical to providing improved therapy5. Here we investigate the cause and consequences of vemurafenib resistance using two independently derived primary human melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumours show continued dependency on BRAF(V600E)→MEK→ERK signalling owing to elevated BRAF(V600E) expression. Most importantly, we demonstrate that vemurafenib-resistant melanomas become drug dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumours. We further demonstrate that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. 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.
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We thank the members of the Novartis Institutes for BioMedical Reseach (NIBR) Pharmacology department for technical support, comments and discussions during the course of this work. We thank C. Voliva, N. Aziz and E. Collisson for discussions. We thank B. Weisburd and the rest of the NIBR Bioinformatics department for assistance with exome sequencing data analysis. We thank S. Kaufman for sharing her knowledge of cell-based assays. We thank V. Marsh, N. Rosen, P. Poulikakos and D. Solit for providing additional advice and reagents. M.D.T. was supported by an NIBR Presidential Postdoctoral Fellowship. M.M. acknowledges support from the Melanoma Research Alliance and the National Cancer Institute (R01-CA176839). A.S.L. was supported by a National Research Service Award T32 training grant HL007185.
The authors declare no competing financial interests.
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Das Thakur, M., Salangsang, F., Landman, A. et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 494, 251–255 (2013). https://doi.org/10.1038/nature11814
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