EMBO Molecular Medicine | |
Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts | |
Kristel Kemper2  Oscar Krijgsman2  Paulien Cornelissen-Steijger2  Aida Shahrabi2  Fleur Weeber2  Ji-Ying Song1  Thomas Kuilman2  Daniel J Vis5  Lodewyk F Wessels5  Emile E Voest2  Ton NM Schumacher4  Christian U Blank4  David J Adams3  John B Haanen4  | |
[1] Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK;Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;Computational Cancer Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands | |
关键词: Melanoma; drug resistance; tumor heterogeneity; patient‐derived xenografts; | |
DOI : 10.15252/emmm.201404914 | |
来源: Wiley | |
【 摘 要 】
The development of targeted inhibitors, like vemurafenib, has greatly improved the clinical outcome of BRAFV600E 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. 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.Abstract
Synopsis
【 授权许可】
CC BY
© 2015 The Authors. Published under the terms of the CC BY 4.0 license
Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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