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

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.

Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management

“…If symptoms persist, corticosteroid-sparing therapies like leflunomide or methotrexate can be applied. Based on findings from in vitro and in vivo models, in which leflunomide prevents melanoma growth in combination with BRAFi+MEKi,58 leflunomide might be preferred.…”

AhR and Cancer: from Gene Profiling to Targeted Therapy

“…The antiinflammatory drug leflunomide, approved for the treatment of rheumatoid arthritis in 1998, has been shown to be an AhR agonist [73]. This molecule shows promise in cancer treatment, notably for melanoma [74] [75], bladder cancer [76], and oral squamous-cell carcinoma [77]. Indirubins E804 (indirubin-3'-(2,3 dihydroxypropyl)-oximether) and 7BIO (7-Bromoindirubin-3′-oxime), synthetic derivatives of natural indirubin, activate AhR and inhibit the synthesis of important proinflammatory cytokines, such as IL-6 and the oncogene STAT3.…”

UVB-induced DHODH upregulation, which is driven by STAT3, is a promising target for chemoprevention and combination therapy of photocarcinogenesis

“…Therefore, the pyrimidine biosynthesis pathway is a promising metabolic target for enhancing the efficacy of chemotherapy and limiting the emergence of resistance. In support of this notion, the combination of doxorubicin and LFN, as well as the combination of MEK inhibitor and LFN have recently been proposed as a promising combination therapy for breast cancer 20 and melanoma 21 , respectively. In line with these data, our results show that if A431 xenografted tumors are subjected to LFN in combination with a genotoxic agent such as 5-FU, a significant synergistic anti-tumor effect occurs (Fig.…”