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Mol Syst Biol. 2015 Mar 26;11(3):797. doi: 10.15252/msb.20145877.

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

Author information

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

PMID:
25814555
PMCID:
PMC4380931
[Indexed for MEDLINE]
Free PMC Article

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