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...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Fallahi‐Sichani, Mohammad [verfasserIn] Becker, Verena [verfasserIn] Izar, Benjamin [verfasserIn] Baker, Gregory J [verfasserIn] Lin, Jia‐Ren [verfasserIn] Boswell, Sarah A [verfasserIn] Shah, Parin [verfasserIn] Rotem, Asaf [verfasserIn] Garraway, Levi A [verfasserIn] Sorger, Peter K [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2017 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2017 |
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| Übergeordnetes Werk: |
Enthalten in: Molecular Systems Biology - Nature Publishing Group UK, 2023, 13(2017), 1 vom: 09. Jan. |
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| Übergeordnetes Werk: |
volume:13 ; year:2017 ; number:1 ; day:09 ; month:01 |
| Links: |
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| DOI / URN: |
10.15252/msb.20166796 |
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| Katalog-ID: |
SPR058028420 |
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| 100 | 1 | |a Fallahi‐Sichani, Mohammad |e verfasserin |0 (orcid)0000-0003-0917-3525 |4 aut | |
| 245 | 1 | 0 | |a Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state |
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| 520 | |a 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. | ||
| 520 | |a Synopsis Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. Cell‐to‐cell variability in BRAFV600E melanomas generates drug‐tolerant subpopulations.The drug‐tolerant, slowly dividing $ NFGR^{High} $ state is transiently heritable.Drugs against a proposed c‐Jun/ECM/FAK/Src cascade block acquisition of this phenotype.The $ NGFR^{High} $ drug‐tolerant state is also blocked by BET inhibitors in vitro and in vivo.Drugs that block adaptation by cell subpopulations increase cell killing by RAF/MEK inhibitors.LINCS‐compliant data and methods are freely available to enhance reproducibility. | ||
| 520 | |a Graphical Abstract Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. | ||
| 650 | 4 | |a adaptive and reversible drug resistance |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a melanomas |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a de‐differentiated NGFR |7 (dpeaa)DE-He213 | |
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| 650 | 4 | |a RAF and MEK inhibitors |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Becker, Verena |e verfasserin |4 aut | |
| 700 | 1 | |a Izar, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Baker, Gregory J |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Jia‐Ren |e verfasserin |4 aut | |
| 700 | 1 | |a Boswell, Sarah A |e verfasserin |0 (orcid)0000-0002-3118-3378 |4 aut | |
| 700 | 1 | |a Shah, Parin |e verfasserin |0 (orcid)0000-0002-7259-1810 |4 aut | |
| 700 | 1 | |a Rotem, Asaf |e verfasserin |0 (orcid)0000-0002-6859-7435 |4 aut | |
| 700 | 1 | |a Garraway, Levi A |e verfasserin |4 aut | |
| 700 | 1 | |a Sorger, Peter K |e verfasserin |0 (orcid)0000-0002-3364-1838 |4 aut | |
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10.15252/msb.20166796 doi (DE-627)SPR058028420 (SPR)msb.20166796-e DE-627 ger DE-627 rakwb eng Fallahi‐Sichani, Mohammad verfasserin (orcid)0000-0003-0917-3525 aut Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2017 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. Synopsis Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. Cell‐to‐cell variability in BRAFV600E melanomas generates drug‐tolerant subpopulations.The drug‐tolerant, slowly dividing $ NFGR^{High} $ state is transiently heritable.Drugs against a proposed c‐Jun/ECM/FAK/Src cascade block acquisition of this phenotype.The $ NGFR^{High} $ drug‐tolerant state is also blocked by BET inhibitors in vitro and in vivo.Drugs that block adaptation by cell subpopulations increase cell killing by RAF/MEK inhibitors.LINCS‐compliant data and methods are freely available to enhance reproducibility. Graphical Abstract Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. adaptive and reversible drug resistance (dpeaa)DE-He213 melanomas (dpeaa)DE-He213 de‐differentiated NGFR (dpeaa)DE-He213 state (dpeaa)DE-He213 RAF and MEK inhibitors (dpeaa)DE-He213 Becker, Verena verfasserin aut Izar, Benjamin verfasserin aut Baker, Gregory J verfasserin aut Lin, Jia‐Ren verfasserin aut Boswell, Sarah A verfasserin (orcid)0000-0002-3118-3378 aut Shah, Parin verfasserin (orcid)0000-0002-7259-1810 aut Rotem, Asaf verfasserin (orcid)0000-0002-6859-7435 aut Garraway, Levi A verfasserin aut Sorger, Peter K verfasserin (orcid)0000-0002-3364-1838 aut Enthalten in Molecular Systems Biology Nature Publishing Group UK, 2023 13(2017), 1 vom: 09. Jan. (DE-627)490536905 (DE-600)2193510-5 1744-4292 nnns volume:13 year:2017 number:1 day:09 month:01 https://dx.doi.org/10.15252/msb.20166796 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2017 1 09 01 |
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10.15252/msb.20166796 doi (DE-627)SPR058028420 (SPR)msb.20166796-e DE-627 ger DE-627 rakwb eng Fallahi‐Sichani, Mohammad verfasserin (orcid)0000-0003-0917-3525 aut Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2017 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. Synopsis Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. Cell‐to‐cell variability in BRAFV600E melanomas generates drug‐tolerant subpopulations.The drug‐tolerant, slowly dividing $ NFGR^{High} $ state is transiently heritable.Drugs against a proposed c‐Jun/ECM/FAK/Src cascade block acquisition of this phenotype.The $ NGFR^{High} $ drug‐tolerant state is also blocked by BET inhibitors in vitro and in vivo.Drugs that block adaptation by cell subpopulations increase cell killing by RAF/MEK inhibitors.LINCS‐compliant data and methods are freely available to enhance reproducibility. Graphical Abstract Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. adaptive and reversible drug resistance (dpeaa)DE-He213 melanomas (dpeaa)DE-He213 de‐differentiated NGFR (dpeaa)DE-He213 state (dpeaa)DE-He213 RAF and MEK inhibitors (dpeaa)DE-He213 Becker, Verena verfasserin aut Izar, Benjamin verfasserin aut Baker, Gregory J verfasserin aut Lin, Jia‐Ren verfasserin aut Boswell, Sarah A verfasserin (orcid)0000-0002-3118-3378 aut Shah, Parin verfasserin (orcid)0000-0002-7259-1810 aut Rotem, Asaf verfasserin (orcid)0000-0002-6859-7435 aut Garraway, Levi A verfasserin aut Sorger, Peter K verfasserin (orcid)0000-0002-3364-1838 aut Enthalten in Molecular Systems Biology Nature Publishing Group UK, 2023 13(2017), 1 vom: 09. Jan. (DE-627)490536905 (DE-600)2193510-5 1744-4292 nnns volume:13 year:2017 number:1 day:09 month:01 https://dx.doi.org/10.15252/msb.20166796 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2017 1 09 01 |
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10.15252/msb.20166796 doi (DE-627)SPR058028420 (SPR)msb.20166796-e DE-627 ger DE-627 rakwb eng Fallahi‐Sichani, Mohammad verfasserin (orcid)0000-0003-0917-3525 aut Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2017 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. Synopsis Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. Cell‐to‐cell variability in BRAFV600E melanomas generates drug‐tolerant subpopulations.The drug‐tolerant, slowly dividing $ NFGR^{High} $ state is transiently heritable.Drugs against a proposed c‐Jun/ECM/FAK/Src cascade block acquisition of this phenotype.The $ NGFR^{High} $ drug‐tolerant state is also blocked by BET inhibitors in vitro and in vivo.Drugs that block adaptation by cell subpopulations increase cell killing by RAF/MEK inhibitors.LINCS‐compliant data and methods are freely available to enhance reproducibility. Graphical Abstract Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. adaptive and reversible drug resistance (dpeaa)DE-He213 melanomas (dpeaa)DE-He213 de‐differentiated NGFR (dpeaa)DE-He213 state (dpeaa)DE-He213 RAF and MEK inhibitors (dpeaa)DE-He213 Becker, Verena verfasserin aut Izar, Benjamin verfasserin aut Baker, Gregory J verfasserin aut Lin, Jia‐Ren verfasserin aut Boswell, Sarah A verfasserin (orcid)0000-0002-3118-3378 aut Shah, Parin verfasserin (orcid)0000-0002-7259-1810 aut Rotem, Asaf verfasserin (orcid)0000-0002-6859-7435 aut Garraway, Levi A verfasserin aut Sorger, Peter K verfasserin (orcid)0000-0002-3364-1838 aut Enthalten in Molecular Systems Biology Nature Publishing Group UK, 2023 13(2017), 1 vom: 09. Jan. (DE-627)490536905 (DE-600)2193510-5 1744-4292 nnns volume:13 year:2017 number:1 day:09 month:01 https://dx.doi.org/10.15252/msb.20166796 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2017 1 09 01 |
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10.15252/msb.20166796 doi (DE-627)SPR058028420 (SPR)msb.20166796-e DE-627 ger DE-627 rakwb eng Fallahi‐Sichani, Mohammad verfasserin (orcid)0000-0003-0917-3525 aut Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2017 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. Synopsis Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. Cell‐to‐cell variability in BRAFV600E melanomas generates drug‐tolerant subpopulations.The drug‐tolerant, slowly dividing $ NFGR^{High} $ state is transiently heritable.Drugs against a proposed c‐Jun/ECM/FAK/Src cascade block acquisition of this phenotype.The $ NGFR^{High} $ drug‐tolerant state is also blocked by BET inhibitors in vitro and in vivo.Drugs that block adaptation by cell subpopulations increase cell killing by RAF/MEK inhibitors.LINCS‐compliant data and methods are freely available to enhance reproducibility. Graphical Abstract Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. adaptive and reversible drug resistance (dpeaa)DE-He213 melanomas (dpeaa)DE-He213 de‐differentiated NGFR (dpeaa)DE-He213 state (dpeaa)DE-He213 RAF and MEK inhibitors (dpeaa)DE-He213 Becker, Verena verfasserin aut Izar, Benjamin verfasserin aut Baker, Gregory J verfasserin aut Lin, Jia‐Ren verfasserin aut Boswell, Sarah A verfasserin (orcid)0000-0002-3118-3378 aut Shah, Parin verfasserin (orcid)0000-0002-7259-1810 aut Rotem, Asaf verfasserin (orcid)0000-0002-6859-7435 aut Garraway, Levi A verfasserin aut Sorger, Peter K verfasserin (orcid)0000-0002-3364-1838 aut Enthalten in Molecular Systems Biology Nature Publishing Group UK, 2023 13(2017), 1 vom: 09. Jan. (DE-627)490536905 (DE-600)2193510-5 1744-4292 nnns volume:13 year:2017 number:1 day:09 month:01 https://dx.doi.org/10.15252/msb.20166796 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2017 1 09 01 |
| allfieldsSound |
10.15252/msb.20166796 doi (DE-627)SPR058028420 (SPR)msb.20166796-e DE-627 ger DE-627 rakwb eng Fallahi‐Sichani, Mohammad verfasserin (orcid)0000-0003-0917-3525 aut Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2017 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. Synopsis Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. Cell‐to‐cell variability in BRAFV600E melanomas generates drug‐tolerant subpopulations.The drug‐tolerant, slowly dividing $ NFGR^{High} $ state is transiently heritable.Drugs against a proposed c‐Jun/ECM/FAK/Src cascade block acquisition of this phenotype.The $ NGFR^{High} $ drug‐tolerant state is also blocked by BET inhibitors in vitro and in vivo.Drugs that block adaptation by cell subpopulations increase cell killing by RAF/MEK inhibitors.LINCS‐compliant data and methods are freely available to enhance reproducibility. Graphical Abstract Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. adaptive and reversible drug resistance (dpeaa)DE-He213 melanomas (dpeaa)DE-He213 de‐differentiated NGFR (dpeaa)DE-He213 state (dpeaa)DE-He213 RAF and MEK inhibitors (dpeaa)DE-He213 Becker, Verena verfasserin aut Izar, Benjamin verfasserin aut Baker, Gregory J verfasserin aut Lin, Jia‐Ren verfasserin aut Boswell, Sarah A verfasserin (orcid)0000-0002-3118-3378 aut Shah, Parin verfasserin (orcid)0000-0002-7259-1810 aut Rotem, Asaf verfasserin (orcid)0000-0002-6859-7435 aut Garraway, Levi A verfasserin aut Sorger, Peter K verfasserin (orcid)0000-0002-3364-1838 aut Enthalten in Molecular Systems Biology Nature Publishing Group UK, 2023 13(2017), 1 vom: 09. Jan. (DE-627)490536905 (DE-600)2193510-5 1744-4292 nnns volume:13 year:2017 number:1 day:09 month:01 https://dx.doi.org/10.15252/msb.20166796 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 13 2017 1 09 01 |
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Enthalten in Molecular Systems Biology 13(2017), 1 vom: 09. Jan. volume:13 year:2017 number:1 day:09 month:01 |
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Enthalten in Molecular Systems Biology 13(2017), 1 vom: 09. Jan. volume:13 year:2017 number:1 day:09 month:01 |
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Fallahi‐Sichani, Mohammad @@aut@@ Becker, Verena @@aut@@ Izar, Benjamin @@aut@@ Baker, Gregory J @@aut@@ Lin, Jia‐Ren @@aut@@ Boswell, Sarah A @@aut@@ Shah, Parin @@aut@@ Rotem, Asaf @@aut@@ Garraway, Levi A @@aut@@ Sorger, Peter K @@aut@@ |
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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.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. Cell‐to‐cell variability in BRAFV600E melanomas generates drug‐tolerant subpopulations.The drug‐tolerant, slowly dividing $ NFGR^{High} $ state is transiently heritable.Drugs against a proposed c‐Jun/ECM/FAK/Src cascade block acquisition of this phenotype.The $ NGFR^{High} $ drug‐tolerant state is also blocked by BET inhibitors in vitro and in vivo.Drugs that block adaptation by cell subpopulations increase cell killing by RAF/MEK inhibitors.LINCS‐compliant data and methods are freely available to enhance reproducibility.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">adaptive and reversible drug resistance</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">melanomas</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">de‐differentiated NGFR</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">state</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">RAF and MEK inhibitors</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Becker, Verena</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Izar, Benjamin</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Baker, Gregory J</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Lin, Jia‐Ren</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Boswell, Sarah A</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-3118-3378</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Shah, Parin</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-7259-1810</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Rotem, Asaf</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-6859-7435</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Garraway, Levi A</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Sorger, Peter K</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0002-3364-1838</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">Molecular Systems Biology</subfield><subfield code="d">Nature Publishing Group UK, 2023</subfield><subfield code="g">13(2017), 1 vom: 09. 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Fallahi‐Sichani, Mohammad |
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Fallahi‐Sichani, Mohammad misc adaptive and reversible drug resistance misc melanomas misc de‐differentiated NGFR misc state misc RAF and MEK inhibitors Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state |
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Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state adaptive and reversible drug resistance (dpeaa)DE-He213 melanomas (dpeaa)DE-He213 de‐differentiated NGFR (dpeaa)DE-He213 state (dpeaa)DE-He213 RAF and MEK inhibitors (dpeaa)DE-He213 |
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misc adaptive and reversible drug resistance misc melanomas misc de‐differentiated NGFR misc state misc RAF and MEK inhibitors |
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Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state |
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Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state |
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Fallahi‐Sichani, Mohammad |
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Molecular Systems Biology |
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Fallahi‐Sichani, Mohammad Becker, Verena Izar, Benjamin Baker, Gregory J Lin, Jia‐Ren Boswell, Sarah A Shah, Parin Rotem, Asaf Garraway, Levi A Sorger, Peter K |
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Fallahi‐Sichani, Mohammad |
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10.15252/msb.20166796 |
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(ORCID)0000-0003-0917-3525 (ORCID)0000-0002-3118-3378 (ORCID)0000-0002-7259-1810 (ORCID)0000-0002-6859-7435 (ORCID)0000-0002-3364-1838 |
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adaptive resistance of melanoma cells to raf inhibition via reversible induction of a slowly dividing de‐differentiated state |
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Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state |
| abstract |
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. Synopsis Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. Cell‐to‐cell variability in BRAFV600E melanomas generates drug‐tolerant subpopulations.The drug‐tolerant, slowly dividing $ NFGR^{High} $ state is transiently heritable.Drugs against a proposed c‐Jun/ECM/FAK/Src cascade block acquisition of this phenotype.The $ NGFR^{High} $ drug‐tolerant state is also blocked by BET inhibitors in vitro and in vivo.Drugs that block adaptation by cell subpopulations increase cell killing by RAF/MEK inhibitors.LINCS‐compliant data and methods are freely available to enhance reproducibility. Graphical Abstract Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. © The Author(s) 2017 |
| abstractGer |
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. Synopsis Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. Cell‐to‐cell variability in BRAFV600E melanomas generates drug‐tolerant subpopulations.The drug‐tolerant, slowly dividing $ NFGR^{High} $ state is transiently heritable.Drugs against a proposed c‐Jun/ECM/FAK/Src cascade block acquisition of this phenotype.The $ NGFR^{High} $ drug‐tolerant state is also blocked by BET inhibitors in vitro and in vivo.Drugs that block adaptation by cell subpopulations increase cell killing by RAF/MEK inhibitors.LINCS‐compliant data and methods are freely available to enhance reproducibility. Graphical Abstract Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. © The Author(s) 2017 |
| abstract_unstemmed |
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. Synopsis Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. Cell‐to‐cell variability in BRAFV600E melanomas generates drug‐tolerant subpopulations.The drug‐tolerant, slowly dividing $ NFGR^{High} $ state is transiently heritable.Drugs against a proposed c‐Jun/ECM/FAK/Src cascade block acquisition of this phenotype.The $ NGFR^{High} $ drug‐tolerant state is also blocked by BET inhibitors in vitro and in vivo.Drugs that block adaptation by cell subpopulations increase cell killing by RAF/MEK inhibitors.LINCS‐compliant data and methods are freely available to enhance reproducibility. Graphical Abstract Responses of BRAFV600E melanoma cells to vemurafenib were studied at the single‐cell level using live‐cell imaging and by transcriptional and biochemical profiling to uncover a slowly dividing, de‐differentiated cell state associated with drug resistance but inhibitable by drug combinations. © The Author(s) 2017 |
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Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state |
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Becker, Verena Izar, Benjamin Baker, Gregory J Lin, Jia‐Ren Boswell, Sarah A Shah, Parin Rotem, Asaf Garraway, Levi A Sorger, Peter K |
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Becker, Verena Izar, Benjamin Baker, Gregory J Lin, Jia‐Ren Boswell, Sarah A Shah, Parin Rotem, Asaf Garraway, Levi A Sorger, Peter K |
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| score |
7.402298 |