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Mol Syst Biol. 2017 Jan 9;13(1):905. doi: 10.15252/msb.20166796.

Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state.

Author information

1
Department of Systems Biology, Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA mohammad_fallahisichani@hms.harvard.edu peter_sorger@hms.harvard.edu.
2
Department of Systems Biology, Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
4
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
5
HMS LINCS Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
6
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.

Abstract

Treatment of BRAF-mutant melanomas with MAP kinase pathway inhibitors is paradigmatic of the promise of precision cancer therapy but also highlights problems with drug resistance that limit patient benefit. We use live-cell imaging, single-cell analysis, and molecular profiling to show that exposure of tumor cells to RAF/MEK inhibitors elicits a heterogeneous response in which some cells die, some arrest, and the remainder adapt to drug. Drug-adapted cells up-regulate markers of the neural crest (e.g., NGFR), a melanocyte precursor, and grow slowly. This phenotype is transiently stable, reverting to the drug-naïve state within 9 days of drug withdrawal. Transcriptional profiling of cell lines and human tumors implicates a c-Jun/ECM/FAK/Src cascade in de-differentiation in about one-third of cell lines studied; drug-induced changes in c-Jun and NGFR levels are also observed in xenograft and human tumors. Drugs targeting the c-Jun/ECM/FAK/Src cascade as well as BET bromodomain inhibitors increase the maximum effect (Emax) of RAF/MEK kinase inhibitors by promoting cell killing. Thus, analysis of reversible drug resistance at a single-cell level identifies signaling pathways and inhibitory drugs missed by assays that focus on cell populations.

KEYWORDS:

BRAFV600E melanomas; RAF and MEK inhibitors; adaptive and reversible drug resistance; de‐differentiated NGFRHigh state

PMID:
28069687
PMCID:
PMC5248573
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