Conclusions
Our study of KIT-mutation-and KITWT-bearing melanomas demonstrates that ponatinib is a far more potent inhibitor than is imatinib for KIT-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 KIT 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.
Methods
A cohort of patient-derived tumor xenograft (PDX) models and corresponding PDX-derived cells (PDCs) from patients with melanomas harboring KIT mutations (KITV560D, KITK642E and KITD816V) were established, characterized, and then used to test the in vitro and, subsequently, in vivo inhibitory effects of a panel of known KIT inhibitors.
Results
Ponatinib was more potent than imatinib against cells bearing KIT mutations. In vivo drug efficacy evaluation experiments showed that ponatinib treatment caused much stronger inhibition of KIT-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 KITD816V mutant protein than does imatinib. Conclusions: Our study of KIT-mutation-and KITWT-bearing melanomas demonstrates that ponatinib is a far more potent inhibitor than is imatinib for KIT-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 KIT 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.