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Systematic Analysis Of BRAFV600E Melanomas Reveals A Role For JNK/c-Jun Pathway In Adaptive Resistance To Drug-induced Apoptosis

M. Fallahi-Sichani, N. Moerke, M. Niepel, T. Zhang, N. Gray, P. Sorger
Published 2015 · Biology, Medicine

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Drugs that inhibit RAF/MEK signaling, such as vemurafenib, elicit profound but often temporary anti‐tumor responses in patients with BRAFV600E melanoma. Adaptive responses to RAF/MEK inhibition occur on a timescale of hours to days, involve homeostatic responses that reactivate MAP kinase signaling and compensatory mitogenic pathways, and attenuate the anti‐tumor effects of RAF/MEK inhibitors. We profile adaptive responses across a panel of melanoma cell lines using multiplex biochemical measurement, single‐cell assays, and statistical modeling and show that adaptation involves at least six signaling cascades that act to reduce drug potency (IC50) and maximal effect (i.e., Emax ≪ 1). Among these cascades, we identify a role for JNK/c‐Jun signaling in vemurafenib adaptation and show that RAF and JNK inhibitors synergize in cell killing. This arises because JNK inhibition prevents a subset of cells in a cycling population from becoming quiescent upon vemurafenib treatment, thereby reducing drug Emax. Our findings demonstrate the breadth and diversity of adaptive responses to RAF/MEK inhibition and a means to identify which steps in a signaling cascade are most predictive of phenotypic response.
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