BRAF Mutation in Melanoma and Dietary Polyphenols as Adjunctive Treatment Strategy
Biochemistry and Molecular Biology
Melanomas are the most insidious type of skin cancers, with more than 76,000 new cases and over 9100 deaths anticipated by 2013 in the United States. Recent advances in an understanding of genetic alterations that cause mutations in the oncogenes BRAF and NRAS, have provided new leads for treatment of melanoma. A valine-to-glutamic acid substitution mutation at position 600 (V600E) in the BRAF kinase gene has been shown to occur in approximately 75% melanoma cases. This mutation results in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, thus offering a target amenable to development of novel therapies and to adjunctive or complementary management options. A number of preclinical and clinical investigations of small molecule inhibitors of BRAF show promise, e.g., Zelboraf, an FDA-approved BRAF inhibitor for the treatment of metastatic melanomas with the V600E mutation. However, drug resistance has been found to occur in some patients. Elucidating possible mechanisms behind resistance and developing therapies to bypass such are important in ensuring the success of BRAF inhibitors. BRAF is strategically positioned at the tip of a signaling cascade that transduces effects through a cadre of downstream targets. Several studies show that these proteins are negatively regulated by a variety of diet-derived polyphenols and suggest that an intervention “cocktail” comprising these components may play be considered for development as “low bioactivity-less resistance inducing” adjunctive treatment of melanoma.
Aquilato, A., Lopez, V., Doonan, B., Hsieh, T. C., Pinto, J. T., Wu, E., & Wu, J. M. (2014). BRAF mutation in melanoma and dietary polyphenols as adjunctive treatment strategy. In R. R. Watson, V. R. Preedy, & S. Zibadi (Eds.), Polyphenols in human health and disease (pp. 1353-1365). doi:10.1016/B978-0-12-398456-2.00102-X