Abstract
Cutaneous melanoma, which develops from the pigment producing cells called melanocytes, is the most deadly form of skin cancer. Unlike the majority of other cancers, the incidence rates of melanoma are still on the rise and the treatment options currently available are being hindered by resistance, limited response rates and adverse toxicity. We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), also holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib. We have further characterized the function of leflunomide and show that the drug reduces the number of viable cells in both wild-type and BRAFV600E mutant melanoma cell lines. Further experiments have revealed leflunomide reduces cell proliferation and causes cells to arrest in G1 of the cell cycle. Cell death assays show leflunomide causes apoptosis at treatment concentrations of 25 and 50 µM. To determine if leflunomide could be used combinatorialy with other anti-melanoma drugs, it was tested in combination with the MEK inhibitor, selumetinib. This combination showed a synergistic effect in the cell lines tested. This drug combination led to an enhanced decrease in tumor size when tested in vivo compared to either drug alone, demonstrating its potential as a novel combinatorial therapy for melanoma.
Highlights
Melanoma is the most deadly form of skin cancer, causing the majority of skin cancer deaths despite only accounting for 5% of reported skin cancer cases (Skin Cancer Foundation, 2017; [1]) and unlike most other cancers, incidence rates are still on the rise
We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib
We have selected a panel of eight human melanoma cell lines to further characterize the potential effects of leflunomide as an anti-melanoma drug (Supplementary Table 1), where half habour the BRAFV600E mutation and the remainder are wildtype for BRAF (BRAFWT; Supplementary Table 1)
Summary
Melanoma is the most deadly form of skin cancer, causing the majority of skin cancer deaths despite only accounting for 5% of reported skin cancer cases (Skin Cancer Foundation, 2017; [1]) and unlike most other cancers, incidence rates are still on the rise. In recent years, a number of new therapies have been developed that provide a better prognosis for patients These include immunotherapies, in particular immune checkpoint inhibitors such as ipilimumab, pembrolizumab and nivolumab that show remarkable clinical responses in some melanoma patients [3,4,5]. These therapies are not without their drawbacks, including immune-related www.impactjournals.com/oncotarget adverse events, limited response rates and possibly therapy-induced acquired resistance, where modifications to improve the clinical application of these treatments are currently ongoing [6]
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