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

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 a remaining fraction adapts to drug. Drug-adapted cells up-regulate markers of the neural crest (e.g. NGFR), a melanocyte precursor, and grow slowly. To identify genes associated with acquisition of the slowly-cycling, vemurafenib-adapted state, we performed RNA sequencing (RNA-seq) on COLO858 cells (that show the slowly-cycling phenotype) exposed to drug for 24 and 48 h; drug-treated MMACSF cells served as a control. Transcriptional profiling implicates a c-Jun/ECM/FAK/Src cascade in adaptive resistance to RAF inhibition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE87641 | GEO | 2016/12/01

SECONDARY ACCESSION(S): PRJNA345487

REPOSITORIES: GEO

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