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

Marlous Hoogstraat, Christa G Gadellaa-van Hooijdonk, Inge Ubink, Nicolle J M Besselink, Mark Pieterse, Wouter Veldhuis, Marijn van Stralen, Eelco F J Meijer, Stefan M Willems, Michael A Hadders, Thomas Kuilman, Oscar Krijgsman, Daniel S Peeper, Marco J Koudijs, Edwin Cuppen, Emile E Voest, Martijn P Lolkema

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14 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)318-323
Number of pages6
JournalPigment cell & melanoma research
Issue number3
Publication statusPublished - 2015
Externally publishedYes


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

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