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

作者：Fallahi Sichani Mohammad^*; Becker Verena; Izar Benjamin; Baker Gregory J; Lin Jia Ren; Boswell Sarah A; Shah Parin; Rotem Asaf; Garraway Levi A; Sorger Peter K^*

来源：Molecular Systems Biology, 2017, 13(1): 905.

DOI：10.15252/msb.20166796

• adaptive and reversible drug resistance
• BRAF(V600E) melanomas
• de-differentiated NGFR(High) state
• RAF and MEK inhibitors

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-naive 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 (E-max) 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.

• 出版日期2017-1
• 单位MIT