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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-01-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.15252/msb.20166796 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Mohammad Fallahi‐Sichani |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0e7952fd9cd14e07ad39e72e947a9f95 |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-0e7952fd9cd14e07ad39e72e947a9f952025-08-20T03:43:37ZengSpringer NatureMolecular Systems Biology1744-42922017-01-0113112410.15252/msb.20166796Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated stateMohammad Fallahi‐Sichani0Verena Becker1Benjamin Izar2Gregory J Baker3Jia‐Ren Lin4Sarah A Boswell5Parin Shah6Asaf Rotem7Levi A Garraway8Peter K Sorger9Department of Systems Biology, Program in Therapeutic Sciences, Harvard Medical SchoolDepartment of Systems Biology, Program in Therapeutic Sciences, Harvard Medical SchoolDepartment of Medical Oncology, Dana–Farber Cancer InstituteDepartment of Systems Biology, Program in Therapeutic Sciences, Harvard Medical SchoolHMS LINCS Center and Laboratory of Systems Pharmacology, Harvard Medical SchoolDepartment of Systems Biology, Program in Therapeutic Sciences, Harvard Medical SchoolDepartment of Medical Oncology, Dana–Farber Cancer InstituteDepartment of Medical Oncology, Dana–Farber Cancer InstituteDepartment of Medical Oncology, Dana–Farber Cancer InstituteDepartment of Systems Biology, Program in Therapeutic Sciences, Harvard Medical SchoolAbstract 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.https://doi.org/10.15252/msb.20166796adaptive and reversible drug resistanceBRAFV600E melanomasde‐differentiated NGFRHigh stateRAF and MEK inhibitors |
| spellingShingle | 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 Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state Molecular Systems Biology adaptive and reversible drug resistance BRAFV600E melanomas de‐differentiated NGFRHigh state RAF and MEK inhibitors |
| title | Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state |
| title_full | Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state |
| title_fullStr | Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state |
| title_full_unstemmed | Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state |
| title_short | Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state |
| title_sort | adaptive resistance of melanoma cells to raf inhibition via reversible induction of a slowly dividing de differentiated state |
| topic | adaptive and reversible drug resistance BRAFV600E melanomas de‐differentiated NGFRHigh state RAF and MEK inhibitors |
| url | https://doi.org/10.15252/msb.20166796 |
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