Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state
Name
Fallahi-Sichani-2017-Adaptive resistance of me.pdf
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2.01 MB
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Author(s)
Becker, Verena
Izar, Benjamin
Baker, Gregory J
Lin, Jia?Ren
Boswell, Sarah A
Shah, Parin
Rotem, Asaf
Sorger, Peter K
Fallahi-Sichani, Mohammad
Garraway, Levi
Date Issued
November 2016
Journal
Molecular Systems Biology
Publisher
Nature Publishing Group
Citation
Fallahi‐Sichani, Mohammad; Becker, Verena; Izar, Benjamin; Baker, Gregory J; Lin, Jia‐Ren; Boswell, Sarah A; Shah, Parin; Rotem, Asaf; Garraway, Levi A and Sorger, Peter K. “Adaptive Resistance of Melanoma Cells to RAF Inhibition via Reversible Induction of a Slowly Dividing De‐differentiated State.” Molecular Systems Biology 13, no. 1 (January 2017): 905 © 2017 The Authors
Version
Final published version
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 (E[subscript 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.
MIT Department
Broad Institute of MIT and Harvard
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Creative Commons Attribution 4.0 International License
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DOI of Published Version
https://doi.org/10.15252/msb.20166796
