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Modeling BRAF inhibitor resistance in melanoma reveals a strategy to forestall drug resistance
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Cancer Science & Therapy

ISSN: 1948-5956

Open Access

Modeling BRAF inhibitor resistance in melanoma reveals a strategy to forestall drug resistance


3rd World Congress on Cancer Science & Therapy

October 21-23, 2013 DoubleTree by Hilton Hotel San Francisco Airport, CA, USA

Martin McMahon, Meghna Das Thakur, Fernando Salansang, Allison Landman, William R. Sellers, Nancy K. Pryer, Mitchel P. Levesque, Reinhard Dummer, Rosalie Fisher, Martin Larkin and Darrin Stuart

Accepted Abstracts: J Cancer Sci Ther

Abstract :

Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with >50% of tumors expressing the BRAFV 600E oncoprotein. Moreover, the marked tumor 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 maintenance. However, since most patients relapse with lethal drug resistant disease, understanding and preventing mechanism(s) of resistance is critical to providing improved therapy. To that end we investigated the causes and consequences of vemurafenib resistance using two independent primary human patient-derived melanoma xenograft models in which drug resistance is selected by continuous vemurafenib administration. In one of these models, resistant tumors show continued dependency on BRAFV 600E →MEK→ERK signaling due to elevated BRAFV 600E 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 tumors. 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 response of melanomas to BRAF inhibitor therapy with the ultimate goal of curative therapy for the subset of BRAF mutated melanoma patients.

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