Theranostics 2019; 9(7):1952-1964. doi:10.7150/thno.30890

Research Paper

Repurposing Ponatinib as a Potent Agent against KIT Mutant Melanomas

Yong Han1,2,3*, Ziyue Gu1,2,3*, Jing Wu1,2,3*, Xiaojuan Huang1,2,3, Rong Zhou1,2,3, Chaoji Shi2, Wenjie Tao1,2,3, Lizhen Wang4, Yanan Wang1, Guoyu Zhou1, Jiang Li4, Zhiyuan Zhang1,2,3✉, Shuyang Sun1,2,3✉

1. Department of Oral and Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China.
2. National Clinical Research Center for Oral Diseases, Shanghai 200011, P.R. China.
3. Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, P.R. China.
4. Department of Oral Pathology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, P.R. China.
*These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Han Y, Gu Z, Wu J, Huang X, Zhou R, Shi C, Tao W, Wang L, Wang Y, Zhou G, Li J, Zhang Z, Sun S. Repurposing Ponatinib as a Potent Agent against KIT Mutant Melanomas. Theranostics 2019; 9(7):1952-1964. doi:10.7150/thno.30890. Available from

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Rationale: Mutations in KIT, 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 KIT-mutation-bearing melanomas that is recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice guidelines. Patients with KIT mutations, however, are either insensitive or rapidly progress to imatinib insensitivity, which restricts its clinical use. Thus, effective inhibitors of KIT-mutation-bearing melanomas are urgently needed.

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.

Keywords: ponatinib, melanomas, KIT, patient-derived xenograft models