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EMBO Mol Med. 2015 Jun 23;7(9):1104-18. doi: 10.15252/emmm.201404914.

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

Author information

  • 1Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 2Division of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 3Computational Cancer Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 4Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 5Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.
  • 6Division of Molecular Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands d.peeper@nki.nl.

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(T55delins) (RT) 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.

KEYWORDS:

Melanoma; drug resistance; patient‐derived xenografts; tumor heterogeneity

PMID:
26105199
PMCID:
PMC4568946
DOI:
10.15252/emmm.201404914
[PubMed - indexed for MEDLINE]
Free PMC Article
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