Exploring BRAF Inhibitor Resistance Mechanisms in Melanoma
Posted: Monday, June 3, 2019
Clearly, BRAF inhibitor therapy improves tumor regression in metastatic melanoma with BRAF V600 mutations, but treatment resistance often persists. According to a review article published in Frontiers in Oncology by Scott A. Koepsell, MD, PhD, and colleague, of the University of Nebraska Medical Center, preclinical studies suggest that the development of such treatment resistance may be more complex than single mutations. Based on clinical studies, genetic alterations activating MAPK/Erk seem to play a part in treatment resistance.
“Future studies of BRAF inhibitor resistance in vitro would benefit from adhering to experimental parameters that reflect development of BRAF inhibitor resistance in patients through using multiple cell lines, fully characterizing the dosing strategy, and reporting the fold change in drug sensitivity,” the authors concluded.
Through a multicenter analysis of BRAF inhibitor–resistant patient tissue samples, several genomic changes were recorded. After disease progression, the analysis detected multiple secondary mutations in the MAPK/Erk signaling pathway, mutant BRAF copy number gains, and BRAF alternative splicing. However, there were no identified resistance drivers in 41.7% of the samples.
The review article focuses in depth on various BRAF inhibitor resistance mechanisms in melanoma cell lines, including receptor tyrosine kinase expression, secondary MAPK/Erk mutations, and alternative resistance pathways. Phenotypic changes in BRAF inhibitor–resistant cell lines, such as increased motility and invasion, are also explored.
Disclosure: The authors reported no conflicts of interest.