title: 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.
abstract: 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.
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands; Netherlands Center for Personalized Cancer Treatment, Utrecht, The Netherlands.
authors.forename: Marlous
authors.initials: M
authors.lastname: Hoogstraat
authors.forename: Christa G
authors.initials: CG
authors.lastname: Gadellaa-van Hooijdonk
authors.forename: Inge
authors.initials: I
authors.lastname: Ubink
authors.forename: Nicolle J M
authors.initials: NJ
authors.lastname: Besselink
authors.forename: Mark
authors.initials: M
authors.lastname: Pieterse
authors.forename: Wouter
authors.initials: W
authors.lastname: Veldhuis
authors.forename: Marijn
authors.initials: M
authors.lastname: van Stralen
authors.forename: Eelco F J
authors.initials: EF
authors.lastname: Meijer
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Willems
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hadders
authors.forename: Thomas
authors.initials: T
authors.lastname: Kuilman
authors.forename: Oscar
authors.initials: O
authors.lastname: Krijgsman
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Peeper
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Koudijs
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
authors.forename: Martijn P
authors.initials: MP
authors.lastname: Lolkema
mesh_terms: D001706:Biopsy; D003952:Diagnostic Imaging; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D018740:Genetic Heterogeneity; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; intratumoral heterogeneity; therapy resistance; vemurafenib; volumetric imaging analysis