期刊
MOLECULAR SYSTEMS BIOLOGY
卷 13, 期 1, 页码 -出版社
WILEY
DOI: 10.15252/msb.20166796
关键词
adaptive and reversible drug resistance; BRAF(V600E) melanomas; de-differentiated NGFR(High) state; RAF and MEK inhibitors
资金
- NIH [U54-HL127365, CA139980, GM107618]
- NCI [K99CA194163]
- Merck Fellowship of the Life Sciences Research Foundation
- Adelson Medical Research Foundation
- Melanoma Research Alliance
- Ludwig Center at Harvard
- DFCI Wong Family Award
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.
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