Detailed imaging and genetic analysis reveal a secondary BRAFL505H resistance mutation and extensive intrapatient heterogeneity in metastatic BRAF mutant melanoma patients treated with vemurafenib |
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| Authors: | 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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| Affiliation: | 1. Department of Medical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands;2. Netherlands Center for Personalized Cancer Treatment, Utrecht, The Netherlands;3. Department of Radiology, University Medical Center Utrecht, Utrecht, The Netherlands;4. Image Sciences Institute, University Medical Center Utrecht, Utrecht, The Netherlands;5. Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands;6. Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands;7. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands |
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| 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. |
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| Keywords: |
BRAF
vemurafenib intratumoral heterogeneity therapy resistance volumetric imaging analysis |
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