Evaluating the Role of HDAC6i in Overcoming Resistance to BRAFi in Melanoma Cancer
Open AccessMelanoma is the deadliest type of skin cancer, and it is estimated that 100,000 people will be diagnosed in 2020. BRAFV600E mutation is found in approximately 50% of melanoma cases. Although targeted therapy with BRAF inhibitor (BRAFi), vemurafenib has shown promising results, some patients do not respond or eventually develop resistance. Therefore, overcoming this resistance and increasing the sensitivity of melanoma cells to BRAFi remains one of the most compelling challenges for these patients. Current efforts include the study of combination therapies that can target multiple pathways, thus increasing sensitivity to these inhibitors and delaying resistance. Epigenetic modifiers, like histone deacetylase six inhibitors (HDAC6i), have been studied since HDAC6 regulates multiple pathways that are important for the development of resistance to BRAFi. In this study, we evaluate the role of the ultra-selective HDAC6i NexturastatA in sensitizing multiple human and mouse melanoma cell lines harboring different genetic alterations to vemurafenib. Through cytotoxicity assays, our findings suggest that each cell line responds differently to both individual therapies with vemurafenib and combination therapy with HDAC6i increasing cytotoxicity compared to BRAFi alone. We observed that mouse melanoma cell lines harboring a PTEN deletion respond well to the combination therapy with HDAC6i, while the human cell lines show decreased cytotoxicity compared to vemurafenib alone. These findings suggest that the mutational signature of the tumor could have an effect on the outcome of targeted therapies, and that it should be taken into consideration to maximize the efficacy of therapy.
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Murtadha_gwu_0075M_15146.pdf | 2020-08-04 | Open Access |
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