Intra‐ and inter‐tumor heterogeneity in a vemurafenib‐resistant melanoma patient and derived xenografts

EMBO Molecular Medicine

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 】

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 BRAF^V600E, we identified a new activating insertion in MEK1. This MEK1^T55delinsRT 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.

【 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.