Repurposing Ponatinib as a Potent Agent against Mutant Melanomas.

Mutations in , a major cancer driver gene, are now considered as important drug targets for the treatment of melanomas arising from mucosal and acral tissues and from chronically sun-damaged sites. At present, imatinib is the only targeted drug for -mutation-bearing melanomas that is recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice guidelines. Patients with mutations, however, are either insensitive or rapidly progress to imatinib insensitivity, which restricts its clinical use. Thus, effective inhibitors of -mutation-bearing melanomas are urgently needed. A cohort of patient-derived tumor xenograft (PDX) models and corresponding PDX-derived cells (PDCs) from patients with melanomas harboring mutations (, and ) were established, characterized, and then used to test the and, subsequently, inhibitory effects of a panel of known inhibitors. Ponatinib was more potent than imatinib against cells bearing mutations. drug efficacy evaluation experiments showed that ponatinib treatment caused much stronger inhibition of -mutation-bearing melanomas than did imatinib. Mechanistically, molecular dynamics (MD) simulations revealed a plausible atomic-level explanation for the observation that ponatinib has a higher affinity for the mutant protein than does imatinib. Our study of -mutation-and -bearing melanomas demonstrates that ponatinib is a far more potent inhibitor than is imatinib for -mutation-bearing melanomas and thus underscores that ponatinib should be given priority consideration for the design of precision treatments for melanoma patients triaged to have mutations. Moreover, our work provides a rationale for undertaking clinical trials to examine the repurposing of ponatinib, which is already approved for use in leukemia, for use in treating a large subset of melanoma patients.