J Cancer 2018; 9(24):4665-4676. doi:10.7150/jca.27295 This issue

Research Paper

Utilization of Reactive Oxygen Species Targeted Therapy to Prolong the Efficacy of BRAF Inhibitors in Melanoma

Long Yuan1, Rosalin Mishra1, Hima Patel1, Safnas Abdulsalam2, Kenneth D. Greis3, Ana Luisa Kadekaro4, Edward J. Merino2, Joan T. Garrett1✉

1. James L. Winkle College of Pharmacy,
2. Department of Chemistry,
3. Department of Cancer Biology,
4. Department of Dermatology, University of Cincinnati, Cincinnati, Ohio

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Yuan L, Mishra R, Patel H, Abdulsalam S, Greis KD, Kadekaro AL, Merino EJ, Garrett JT. Utilization of Reactive Oxygen Species Targeted Therapy to Prolong the Efficacy of BRAF Inhibitors in Melanoma. J Cancer 2018; 9(24):4665-4676. doi:10.7150/jca.27295. Available from https://www.jcancer.org/v09p4665.htm

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BRAF mutations occur in about 50% of melanoma patients. FDA approved BRAF and MEK inhibitors have improved the prognosis of patients with BRAF mutations. However, all responders develop resistance typically within one year of treatment. Recent observations demonstrate that BRAF inhibitors induce reactive oxygen species (ROS) in melanoma cells. A100, identified from a library screen, is a ROS-activated prodrug that self-cyclizes into a stable bicyclic ring and causes DNA double strand breaks. We proposed to examine if ROS activated therapy will inhibit tumor growth and evade resistance to BRAF inhibitors. In this study, the BRAF inhibitor dabrafenib was used to generate resistant cell lines (A375DR, SK-MEL-24DR and WM-115DR). Flow cytometry experiments showed that ROS levels are increased in these dabrafenib-resistant cells as compared to parental cells, assessed by both the H2DCFDA and MitoSOX assays. Furthermore, we observed that resistant cells had increased levels of the mitochondrial enzymes SOD2 and PRDX1, which function to reduce ROS levels in the mitochondria. We found that A100 sensitized the resistant melanoma cells to dabrafenib and induced DNA damage. Co-treatment of both A100 and dabrafenib significantly suppressed in vitro cell proliferation and three- dimensional (3D) matrigel growth. This study suggests that the combination of A100 with a BRAF inhibitor could be a potential strategy to treat melanoma patients with BRAF mutations.

Keywords: BRAF, melanoma, dabrafenib, A100, targeted therapy