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  2. Systematic analysis of BRAF(V600E) melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis

Systematic analysis of BRAF(V600E) melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis

  • Mol Syst Biol. 2015 Mar 26;11(3):797. doi: 10.15252/msb.20145877.
Mohammad Fallahi-Sichani 1 Nathan J Moerke 1 Mario Niepel 1 Tinghu Zhang 2 Nathanael S Gray 2 Peter K Sorger 3
Affiliations

Affiliations

  • 1 HMS LINCS Center, Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
  • 2 Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3 HMS LINCS Center, Department of Systems Biology, Harvard Medical School, Boston, MA, USA peter_sorger@hms.harvard.edu.
Abstract

Drugs that inhibit Raf/MEK signaling, such as vemurafenib, elicit profound but often temporary anti-tumor responses in patients with BRaf(V) (600E) 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.

Keywords

BRAFV600E melanomas; RAF and MEK inhibitors; adaptive responses; cell‐to‐cell variability; submaximal drug effect.

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