Send to

Choose Destination
See comment in PubMed Commons below
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

Department of Systems Biology, Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA
Department of Systems Biology, Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
HMS LINCS Center and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA, USA.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA, USA.


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.


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

[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center