The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth

Kimberley Hanson, Stephen Robinson, Karamallah Al-Yousuf, Adam Hendry, Darren Sexton, Victoria Sherwood, Grant Wheeler

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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 to cause 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 tumour size when tested in vivo compared to either drug alone, demonstrating its potential as a novel combinatorial therapy for melanoma.
Original languageEnglish
Pages (from-to)3815-3829
JournalOncotarget
Volume9
Early online date17 Dec 2017
DOIs
Publication statusPublished - 2018

Keywords

  • Melanoma
  • Leflunomide
  • Selumetinib
  • MEK inhibitors
  • Combinatorial therapy

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