دورية أكاديمية
Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state
| العنوان: | Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state |
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| المؤلفون: | Mohammad Fallahi‐Sichani, Verena Becker, Benjamin Izar, Gregory J Baker, Jia‐Ren Lin, Sarah A Boswell, Parin Shah, Asaf Rotem, Levi A Garraway, Peter K Sorger |
| المصدر: | Molecular Systems Biology, Vol 13, Iss 1, Pp n/a-n/a (2017) |
| بيانات النشر: | Springer Nature, 2017. |
| سنة النشر: | 2017 |
| المجموعة: | LCC:Biology (General) LCC:Medicine (General) |
| مصطلحات موضوعية: | adaptive and reversible drug resistance, BRAFV600E melanomas, de‐differentiated NGFRHigh state, RAF and MEK inhibitors, Biology (General), QH301-705.5, Medicine (General), R5-920 |
| الوصف: | 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 (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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1744-4292 20166796 |
| العلاقة: | https://doaj.org/toc/1744-4292Test |
| DOI: | 10.15252/msb.20166796 |
| الوصول الحر: | https://doaj.org/article/0e7952fd9cd14e07ad39e72e947a9f95Test |
| رقم الانضمام: | edsdoj.0e7952fd9cd14e07ad39e72e947a9f95 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 17444292 20166796 |
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| DOI: | 10.15252/msb.20166796 |