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
Hoogstraat, Marlous; Gadellaa-van Hooijdonk, Christa G.; Ubink, Inge; Besselink, Nicolle J. M.; Pieterse, Mark; Veldhuis, Wouter; van Stralen, Marijn; Meijer, Eelco F. J.; Willems, Stefan M.; Hadders, Michael A.; Kuilman, Thomas; Krijgsman, Oscar; Peeper, Daniel S.; Koudijs, Marco J.; Cuppen, Edwin; Voest, Emile E.; Lolkema, Martijn P.
(2015) Pigment Cell and Melanoma Research, volume 28, issue 3, pp. 318 - 323
(Article)
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
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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.
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Keywords: BRAF, vemurafenib, intratumoral heterogeneity, therapy resistance, volumetric imaging analysis, GASTROINTESTINAL STROMAL TUMOR, ACQUIRED-RESISTANCE, RAF INHIBITION, CLONAL EVOLUTION, KINASE DOMAIN, MECHANISMS, IDENTIFICATION, IMATINIB, CANCER, DISPARITY, Journal Article, Research Support, Non-U.S. Gov't
ISSN: 1755-1471
Publisher: Wiley-Blackwell
(Peer reviewed)