Detailed imaging and genetic analysis reveal a secondary BRAF(L505H) resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib

Pigment Cell Melanoma Res. 2015 May;28(3):318-23. doi: 10.1111/pcmr.12347. Epub 2015 Jan 7.


Resistance to treatment is the main problem of targeted treatment for cancer. We followed ten patients during treatment with vemurafenib, by three-dimensional imaging. In all patients, only a subset of lesions progressed. Next-generation DNA sequencing was performed on sequential biopsies in four patients to uncover mechanisms of resistance. In two patients, we identified mutations that explained resistance to vemurafenib; one of these patients had a secondary BRAF L505H mutation. This is the first observation of a secondary BRAF mutation in a vemurafenib-resistant patient-derived melanoma sample, which confirms the potential importance of the BRAF L505H mutation in the development of therapy resistance. Moreover, this study hints toward an important role for tumor heterogeneity in determining the outcome of targeted treatments.

Keywords: BRAF; intratumoral heterogeneity; therapy resistance; vemurafenib; volumetric imaging analysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy
  • Diagnostic Imaging*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Genetic Heterogeneity*
  • Humans
  • Indoles / pharmacology
  • Indoles / therapeutic use*
  • Melanoma / drug therapy*
  • Melanoma / genetics
  • Melanoma / pathology
  • Mutation / genetics*
  • Neoplasm Metastasis
  • Proto-Oncogene Proteins B-raf / genetics*
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use*
  • Vemurafenib


  • Indoles
  • Sulfonamides
  • Vemurafenib
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf