Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts
Abstract The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of $ BRAF^{V600E} $ metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole‐exome sequencing and functional analyses, we have investigated the...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Kemper, Kristel [verfasserIn] Krijgsman, Oscar [verfasserIn] Cornelissen‐Steijger, Paulien [verfasserIn] Shahrabi, Aida [verfasserIn] Weeber, Fleur [verfasserIn] Song, Ji‐Ying [verfasserIn] Kuilman, Thomas [verfasserIn] Vis, Daniel J [verfasserIn] Wessels, Lodewyk F [verfasserIn] Voest, Emile E [verfasserIn] Schumacher, Ton NM [verfasserIn] Blank, Christian U [verfasserIn] Adams, David J [verfasserIn] Haanen, John B [verfasserIn] Peeper, Daniel S [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2015 |
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| Anmerkung: |
© The Authors. Published under the terms of the CC BY 4.0 license 2015 |
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| Übergeordnetes Werk: |
Enthalten in: EMBO Molecular Medicine - Nature Publishing Group UK, 2023, 7(2015), 9 vom: 23. Juni, Seite 1104-1118 |
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| Übergeordnetes Werk: |
volume:7 ; year:2015 ; number:9 ; day:23 ; month:06 ; pages:1104-1118 |
| Links: |
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| DOI / URN: |
10.15252/emmm.201404914 |
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| Katalog-ID: |
SPR057959080 |
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| 100 | 1 | |a Kemper, Kristel |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts |
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| 500 | |a © The Authors. Published under the terms of the CC BY 4.0 license 2015 | ||
| 520 | |a Abstract The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of $ BRAF^{V600E} $ metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole‐exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug‐resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAFV600E, we identified a new activating insertion in MEK1. This MEK1T55delinsRT mutation could be traced back to a fraction of the pre‐treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient‐derived xenografts (PDX) from therapy‐refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter‐ and intra‐tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma. | ||
| 520 | |a Synopsis Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Resistance to targeted therapy is genetically heterogeneous, both within and among metastases.A new 3‐bp insertion in the MEK1 gene ($ MEK1^{T55delinsRT} $) confers resistance to vemurafenib.The $ MEK1^{T55delinsRT} $ mutation can be traced back to a fraction of the pre‐treatment tumor.Tumor heterogeneity was only partially recapitulated in corresponding patient‐derived xenografts. | ||
| 520 | |a Graphical Abstract Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. | ||
| 650 | 4 | |a Melanoma |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a drug resistance |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a tumor heterogeneity |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a patient‐derived xenografts |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Krijgsman, Oscar |e verfasserin |4 aut | |
| 700 | 1 | |a Cornelissen‐Steijger, Paulien |e verfasserin |4 aut | |
| 700 | 1 | |a Shahrabi, Aida |e verfasserin |4 aut | |
| 700 | 1 | |a Weeber, Fleur |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Ji‐Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Kuilman, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Vis, Daniel J |e verfasserin |4 aut | |
| 700 | 1 | |a Wessels, Lodewyk F |e verfasserin |4 aut | |
| 700 | 1 | |a Voest, Emile E |e verfasserin |4 aut | |
| 700 | 1 | |a Schumacher, Ton NM |e verfasserin |4 aut | |
| 700 | 1 | |a Blank, Christian U |e verfasserin |4 aut | |
| 700 | 1 | |a Adams, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Haanen, John B |e verfasserin |4 aut | |
| 700 | 1 | |a Peeper, Daniel S |e verfasserin |4 aut | |
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2015 |
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10.15252/emmm.201404914 doi (DE-627)SPR057959080 (SPR)emmm.201404914-e DE-627 ger DE-627 rakwb eng Kemper, Kristel verfasserin aut Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors. Published under the terms of the CC BY 4.0 license 2015 Abstract The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of $ BRAF^{V600E} $ metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole‐exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug‐resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAFV600E, we identified a new activating insertion in MEK1. This MEK1T55delinsRT mutation could be traced back to a fraction of the pre‐treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient‐derived xenografts (PDX) from therapy‐refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter‐ and intra‐tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma. Synopsis Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Resistance to targeted therapy is genetically heterogeneous, both within and among metastases.A new 3‐bp insertion in the MEK1 gene ($ MEK1^{T55delinsRT} $) confers resistance to vemurafenib.The $ MEK1^{T55delinsRT} $ mutation can be traced back to a fraction of the pre‐treatment tumor.Tumor heterogeneity was only partially recapitulated in corresponding patient‐derived xenografts. Graphical Abstract Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Melanoma (dpeaa)DE-He213 drug resistance (dpeaa)DE-He213 tumor heterogeneity (dpeaa)DE-He213 patient‐derived xenografts (dpeaa)DE-He213 Krijgsman, Oscar verfasserin aut Cornelissen‐Steijger, Paulien verfasserin aut Shahrabi, Aida verfasserin aut Weeber, Fleur verfasserin aut Song, Ji‐Ying verfasserin aut Kuilman, Thomas verfasserin aut Vis, Daniel J verfasserin aut Wessels, Lodewyk F verfasserin aut Voest, Emile E verfasserin aut Schumacher, Ton NM verfasserin aut Blank, Christian U verfasserin aut Adams, David J verfasserin aut Haanen, John B verfasserin aut Peeper, Daniel S verfasserin aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 7(2015), 9 vom: 23. Juni, Seite 1104-1118 (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:7 year:2015 number:9 day:23 month:06 pages:1104-1118 https://dx.doi.org/10.15252/emmm.201404914 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_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 7 2015 9 23 06 1104-1118 |
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10.15252/emmm.201404914 doi (DE-627)SPR057959080 (SPR)emmm.201404914-e DE-627 ger DE-627 rakwb eng Kemper, Kristel verfasserin aut Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors. Published under the terms of the CC BY 4.0 license 2015 Abstract The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of $ BRAF^{V600E} $ metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole‐exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug‐resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAFV600E, we identified a new activating insertion in MEK1. This MEK1T55delinsRT mutation could be traced back to a fraction of the pre‐treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient‐derived xenografts (PDX) from therapy‐refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter‐ and intra‐tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma. Synopsis Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Resistance to targeted therapy is genetically heterogeneous, both within and among metastases.A new 3‐bp insertion in the MEK1 gene ($ MEK1^{T55delinsRT} $) confers resistance to vemurafenib.The $ MEK1^{T55delinsRT} $ mutation can be traced back to a fraction of the pre‐treatment tumor.Tumor heterogeneity was only partially recapitulated in corresponding patient‐derived xenografts. Graphical Abstract Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Melanoma (dpeaa)DE-He213 drug resistance (dpeaa)DE-He213 tumor heterogeneity (dpeaa)DE-He213 patient‐derived xenografts (dpeaa)DE-He213 Krijgsman, Oscar verfasserin aut Cornelissen‐Steijger, Paulien verfasserin aut Shahrabi, Aida verfasserin aut Weeber, Fleur verfasserin aut Song, Ji‐Ying verfasserin aut Kuilman, Thomas verfasserin aut Vis, Daniel J verfasserin aut Wessels, Lodewyk F verfasserin aut Voest, Emile E verfasserin aut Schumacher, Ton NM verfasserin aut Blank, Christian U verfasserin aut Adams, David J verfasserin aut Haanen, John B verfasserin aut Peeper, Daniel S verfasserin aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 7(2015), 9 vom: 23. Juni, Seite 1104-1118 (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:7 year:2015 number:9 day:23 month:06 pages:1104-1118 https://dx.doi.org/10.15252/emmm.201404914 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_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 7 2015 9 23 06 1104-1118 |
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10.15252/emmm.201404914 doi (DE-627)SPR057959080 (SPR)emmm.201404914-e DE-627 ger DE-627 rakwb eng Kemper, Kristel verfasserin aut Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors. Published under the terms of the CC BY 4.0 license 2015 Abstract The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of $ BRAF^{V600E} $ metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole‐exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug‐resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAFV600E, we identified a new activating insertion in MEK1. This MEK1T55delinsRT mutation could be traced back to a fraction of the pre‐treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient‐derived xenografts (PDX) from therapy‐refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter‐ and intra‐tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma. Synopsis Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Resistance to targeted therapy is genetically heterogeneous, both within and among metastases.A new 3‐bp insertion in the MEK1 gene ($ MEK1^{T55delinsRT} $) confers resistance to vemurafenib.The $ MEK1^{T55delinsRT} $ mutation can be traced back to a fraction of the pre‐treatment tumor.Tumor heterogeneity was only partially recapitulated in corresponding patient‐derived xenografts. Graphical Abstract Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Melanoma (dpeaa)DE-He213 drug resistance (dpeaa)DE-He213 tumor heterogeneity (dpeaa)DE-He213 patient‐derived xenografts (dpeaa)DE-He213 Krijgsman, Oscar verfasserin aut Cornelissen‐Steijger, Paulien verfasserin aut Shahrabi, Aida verfasserin aut Weeber, Fleur verfasserin aut Song, Ji‐Ying verfasserin aut Kuilman, Thomas verfasserin aut Vis, Daniel J verfasserin aut Wessels, Lodewyk F verfasserin aut Voest, Emile E verfasserin aut Schumacher, Ton NM verfasserin aut Blank, Christian U verfasserin aut Adams, David J verfasserin aut Haanen, John B verfasserin aut Peeper, Daniel S verfasserin aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 7(2015), 9 vom: 23. Juni, Seite 1104-1118 (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:7 year:2015 number:9 day:23 month:06 pages:1104-1118 https://dx.doi.org/10.15252/emmm.201404914 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_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 7 2015 9 23 06 1104-1118 |
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10.15252/emmm.201404914 doi (DE-627)SPR057959080 (SPR)emmm.201404914-e DE-627 ger DE-627 rakwb eng Kemper, Kristel verfasserin aut Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors. Published under the terms of the CC BY 4.0 license 2015 Abstract The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of $ BRAF^{V600E} $ metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole‐exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug‐resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAFV600E, we identified a new activating insertion in MEK1. This MEK1T55delinsRT mutation could be traced back to a fraction of the pre‐treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient‐derived xenografts (PDX) from therapy‐refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter‐ and intra‐tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma. Synopsis Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Resistance to targeted therapy is genetically heterogeneous, both within and among metastases.A new 3‐bp insertion in the MEK1 gene ($ MEK1^{T55delinsRT} $) confers resistance to vemurafenib.The $ MEK1^{T55delinsRT} $ mutation can be traced back to a fraction of the pre‐treatment tumor.Tumor heterogeneity was only partially recapitulated in corresponding patient‐derived xenografts. Graphical Abstract Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Melanoma (dpeaa)DE-He213 drug resistance (dpeaa)DE-He213 tumor heterogeneity (dpeaa)DE-He213 patient‐derived xenografts (dpeaa)DE-He213 Krijgsman, Oscar verfasserin aut Cornelissen‐Steijger, Paulien verfasserin aut Shahrabi, Aida verfasserin aut Weeber, Fleur verfasserin aut Song, Ji‐Ying verfasserin aut Kuilman, Thomas verfasserin aut Vis, Daniel J verfasserin aut Wessels, Lodewyk F verfasserin aut Voest, Emile E verfasserin aut Schumacher, Ton NM verfasserin aut Blank, Christian U verfasserin aut Adams, David J verfasserin aut Haanen, John B verfasserin aut Peeper, Daniel S verfasserin aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 7(2015), 9 vom: 23. Juni, Seite 1104-1118 (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:7 year:2015 number:9 day:23 month:06 pages:1104-1118 https://dx.doi.org/10.15252/emmm.201404914 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_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 7 2015 9 23 06 1104-1118 |
| allfieldsSound |
10.15252/emmm.201404914 doi (DE-627)SPR057959080 (SPR)emmm.201404914-e DE-627 ger DE-627 rakwb eng Kemper, Kristel verfasserin aut Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts 2015 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors. Published under the terms of the CC BY 4.0 license 2015 Abstract The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of $ BRAF^{V600E} $ metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole‐exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug‐resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAFV600E, we identified a new activating insertion in MEK1. This MEK1T55delinsRT mutation could be traced back to a fraction of the pre‐treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient‐derived xenografts (PDX) from therapy‐refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter‐ and intra‐tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma. Synopsis Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Resistance to targeted therapy is genetically heterogeneous, both within and among metastases.A new 3‐bp insertion in the MEK1 gene ($ MEK1^{T55delinsRT} $) confers resistance to vemurafenib.The $ MEK1^{T55delinsRT} $ mutation can be traced back to a fraction of the pre‐treatment tumor.Tumor heterogeneity was only partially recapitulated in corresponding patient‐derived xenografts. Graphical Abstract Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Melanoma (dpeaa)DE-He213 drug resistance (dpeaa)DE-He213 tumor heterogeneity (dpeaa)DE-He213 patient‐derived xenografts (dpeaa)DE-He213 Krijgsman, Oscar verfasserin aut Cornelissen‐Steijger, Paulien verfasserin aut Shahrabi, Aida verfasserin aut Weeber, Fleur verfasserin aut Song, Ji‐Ying verfasserin aut Kuilman, Thomas verfasserin aut Vis, Daniel J verfasserin aut Wessels, Lodewyk F verfasserin aut Voest, Emile E verfasserin aut Schumacher, Ton NM verfasserin aut Blank, Christian U verfasserin aut Adams, David J verfasserin aut Haanen, John B verfasserin aut Peeper, Daniel S verfasserin aut Enthalten in EMBO Molecular Medicine Nature Publishing Group UK, 2023 7(2015), 9 vom: 23. Juni, Seite 1104-1118 (DE-627)594772761 (DE-600)2485479-7 1757-4684 nnns volume:7 year:2015 number:9 day:23 month:06 pages:1104-1118 https://dx.doi.org/10.15252/emmm.201404914 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 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_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 7 2015 9 23 06 1104-1118 |
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Enthalten in EMBO Molecular Medicine 7(2015), 9 vom: 23. Juni, Seite 1104-1118 volume:7 year:2015 number:9 day:23 month:06 pages:1104-1118 |
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Enthalten in EMBO Molecular Medicine 7(2015), 9 vom: 23. Juni, Seite 1104-1118 volume:7 year:2015 number:9 day:23 month:06 pages:1104-1118 |
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Kemper, Kristel @@aut@@ Krijgsman, Oscar @@aut@@ Cornelissen‐Steijger, Paulien @@aut@@ Shahrabi, Aida @@aut@@ Weeber, Fleur @@aut@@ Song, Ji‐Ying @@aut@@ Kuilman, Thomas @@aut@@ Vis, Daniel J @@aut@@ Wessels, Lodewyk F @@aut@@ Voest, Emile E @@aut@@ Schumacher, Ton NM @@aut@@ Blank, Christian U @@aut@@ Adams, David J @@aut@@ Haanen, John B @@aut@@ Peeper, Daniel S @@aut@@ |
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Published under the terms of the CC BY 4.0 license 2015</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of $ BRAF^{V600E} $ metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole‐exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug‐resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAFV600E, we identified a new activating insertion in MEK1. This MEK1T55delinsRT mutation could be traced back to a fraction of the pre‐treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient‐derived xenografts (PDX) from therapy‐refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter‐ and intra‐tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Resistance to targeted therapy is genetically heterogeneous, both within and among metastases.A new 3‐bp insertion in the MEK1 gene ($ MEK1^{T55delinsRT} $) confers resistance to vemurafenib.The $ MEK1^{T55delinsRT} $ mutation can be traced back to a fraction of the pre‐treatment tumor.Tumor heterogeneity was only partially recapitulated in corresponding patient‐derived xenografts.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. 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Kemper, Kristel |
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Kemper, Kristel misc Melanoma misc drug resistance misc tumor heterogeneity misc patient‐derived xenografts Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts |
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Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts Melanoma (dpeaa)DE-He213 drug resistance (dpeaa)DE-He213 tumor heterogeneity (dpeaa)DE-He213 patient‐derived xenografts (dpeaa)DE-He213 |
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Kemper, Kristel Krijgsman, Oscar Cornelissen‐Steijger, Paulien Shahrabi, Aida Weeber, Fleur Song, Ji‐Ying Kuilman, Thomas Vis, Daniel J Wessels, Lodewyk F Voest, Emile E Schumacher, Ton NM Blank, Christian U Adams, David J Haanen, John B Peeper, Daniel S |
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intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts |
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Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts |
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Abstract The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of $ BRAF^{V600E} $ metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole‐exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug‐resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAFV600E, we identified a new activating insertion in MEK1. This MEK1T55delinsRT mutation could be traced back to a fraction of the pre‐treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient‐derived xenografts (PDX) from therapy‐refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter‐ and intra‐tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma. Synopsis Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Resistance to targeted therapy is genetically heterogeneous, both within and among metastases.A new 3‐bp insertion in the MEK1 gene ($ MEK1^{T55delinsRT} $) confers resistance to vemurafenib.The $ MEK1^{T55delinsRT} $ mutation can be traced back to a fraction of the pre‐treatment tumor.Tumor heterogeneity was only partially recapitulated in corresponding patient‐derived xenografts. Graphical Abstract Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. © The Authors. Published under the terms of the CC BY 4.0 license 2015 |
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Abstract The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of $ BRAF^{V600E} $ metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole‐exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug‐resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAFV600E, we identified a new activating insertion in MEK1. This MEK1T55delinsRT mutation could be traced back to a fraction of the pre‐treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient‐derived xenografts (PDX) from therapy‐refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter‐ and intra‐tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma. Synopsis Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Resistance to targeted therapy is genetically heterogeneous, both within and among metastases.A new 3‐bp insertion in the MEK1 gene ($ MEK1^{T55delinsRT} $) confers resistance to vemurafenib.The $ MEK1^{T55delinsRT} $ mutation can be traced back to a fraction of the pre‐treatment tumor.Tumor heterogeneity was only partially recapitulated in corresponding patient‐derived xenografts. Graphical Abstract Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. © The Authors. Published under the terms of the CC BY 4.0 license 2015 |
| abstract_unstemmed |
Abstract The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of $ BRAF^{V600E} $ metastatic melanoma. However, resistance to such compounds represents a formidable problem. Using whole‐exome sequencing and functional analyses, we have investigated the nature and pleiotropy of vemurafenib resistance in a melanoma patient carrying multiple drug‐resistant metastases. Resistance was caused by a plethora of mechanisms, all of which reactivated the MAPK pathway. In addition to three independent amplifications and an aberrant form of BRAFV600E, we identified a new activating insertion in MEK1. This MEK1T55delinsRT mutation could be traced back to a fraction of the pre‐treatment lesion and not only provided protection against vemurafenib but also promoted local invasion of transplanted melanomas. Analysis of patient‐derived xenografts (PDX) from therapy‐refractory metastases revealed that multiple resistance mechanisms were present within one metastasis. This heterogeneity, both inter‐ and intra‐tumorally, caused an incomplete capture in the PDX of the resistance mechanisms observed in the patient. In conclusion, vemurafenib resistance in a single patient can be established through distinct events, which may be preexisting. Furthermore, our results indicate that PDX may not harbor the full genetic heterogeneity seen in the patient's melanoma. Synopsis Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. Resistance to targeted therapy is genetically heterogeneous, both within and among metastases.A new 3‐bp insertion in the MEK1 gene ($ MEK1^{T55delinsRT} $) confers resistance to vemurafenib.The $ MEK1^{T55delinsRT} $ mutation can be traced back to a fraction of the pre‐treatment tumor.Tumor heterogeneity was only partially recapitulated in corresponding patient‐derived xenografts. Graphical Abstract Vemurafenib resistance in melanoma is caused by different mechanisms occurring independently in each metastasis, some of which exist pre‐treatment. These findings bear several clinical implications in designing treatment strategies. © The Authors. Published under the terms of the CC BY 4.0 license 2015 |
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Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts |
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Krijgsman, Oscar Cornelissen‐Steijger, Paulien Shahrabi, Aida Weeber, Fleur Song, Ji‐Ying Kuilman, Thomas Vis, Daniel J Wessels, Lodewyk F Voest, Emile E Schumacher, Ton NM Blank, Christian U Adams, David J Haanen, John B Peeper, Daniel S |
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10.15252/emmm.201404914 |
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2024-10-22T04:52:33.780Z |
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| score |
7.4014635 |