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 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 l

SUBMITTER: Kemper K 

PROVIDER: S-EPMC4568946 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature