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|Ref Type||Journal Article|
|Authors||Hoogstraat M, Gadellaa-van Hooijdonk CG, Ubink I, Besselink NJ, Pieterse M, Veldhuis W, van Stralen M, Meijer EF, Willems SM, Hadders MA, Kuilman T, Krijgsman O, Peeper DS, Koudijs MJ, Cuppen E, Voest EE, Lolkema MP|
|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.|
|Journal||Pigment cell & melanoma research|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|BRAF L505H BRAF V600E||melanoma||predicted - resistant||Vemurafenib||Case Reports/Case Series||Actionable||In a clinical case study, a melanoma patient harboring BRAF V600E treated with Zelboraf (vemurafenib) subsequently demonstrated resistance likely due to the secondary resistance mutation, BRAF L505H (PMID: 25515853).||25515853|