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

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.

Source: Molecular Systems Biology - January 8, 2017 Category: Molecular Biology Authors: Fallahi-Sichani, M., Becker, V., Izar, B., Baker, G. J., Lin, J.-R., Boswell, S. A., Shah, P., Rotem, A., Garraway, L. A., Sorger, P. K. Tags: Molecular Biology of Disease, Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research