Tunable-combinatorial Mechanisms of Acquired Resistance Limit the Efficacy of BRAF/MEK Co-targeting but Result in Melanoma Drug Addiction

Combined BRAF and MEK targeted therapy improves upon BRAF inhibitor (BRAFi) therapy but is still beset by acquired resistance. We show that melanomas acquire resistance to combined BRAF and MEK inhibition by augmenting or combining mechanisms of single-agent BRAFi resistance. These double-drug resistance-associated genetic configurations significantly altered molecular interactions underlying MAPK pathway reactivation. V600E BRAF, expressed at supra-physiological levels because of V600E BRAF ultra-amplification, dimerized with and activated CRAF. In addition, MEK mutants enhanced interaction with over-expressed V600E BRAF via a regulatory interface at R662 of V600E BRAF. Importantly, melanoma cell lines selected for resistance to BRAFi+MEKi, but not those to BRAFi alone, displayed robust drug addiction, providing a potentially exploitable therapeutic opportunity.