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KIT as an Oncogenic Driver in Melanoma: An Update on Clinical Development

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Abstract

Metastatic melanoma is a heterogenous disease that has served as a model for the development of both targeted therapy and immunotherapy. KIT-mutated melanoma represents a rare subset, most commonly arising from acral, mucosal, and chronically sun-damaged skin. Additionally, KIT alterations are enriched in the triple wild-type subtype of cutaneous melanoma. Activating alterations of KIT—a transmembrane receptor tyrosine kinase important for cell development, growth, and differentiation—have been shown to be critical to oncogenesis across many tumor subtypes. Following the successes of BRAF-targeted therapy in melanoma and KIT-targeted therapy in gastrointestinal stromal tumors, small-molecule tyrosine kinase inhibitors targeting KIT have been examined in KIT-mutated melanoma. KIT inhibitors that have been investigated in relevant clinical trials in advanced melanoma include imatinib, sunitinib, dasatinib, and nilotinib. In these studies, selected patients with KIT-mutated melanoma were shown to be responsive to therapy with KIT inhibition, especially patients with L576P and K642E mutations. This has led to the incorporation of KIT-targeted therapy in the National Comprehensive Cancer Network guidelines for systemic therapy for metastatic or unresectable melanoma. Current research and development efforts include novel KIT-targeted therapies and testing KIT inhibitors in combination with immunotherapy.

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Acknowledgements

The results published or shown here are in part based upon data generated by The Cancer Genome Atlas (TCGA) research network: http://cancergenome.nih.gov/.

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  1. Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA

    Da Meng

  2. Division of Hematology/Oncology, Department of Medicine, Columbia University Irving Medical Center and the Herbert Irving Comprehensive Cancer Center, New York, NY, USA

    Richard D. Carvajal

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Da Meng was funded by the Columbia University Vagelos College of Physicians and Surgeons 2018 Summer Research Program for the preparation of this manuscript.

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Richard D. Carvajal is a consultant for AstraZeneca, Bristol-Myers Squibb, Castle Biosciences, Foundation Medicine, Immunocore, Incyte Merck, Novartis, Roche/Genentech, Aura Biosciences, Chimeron, and Rgenix. Da Meng has no conflicts of interest that might be relevant to the contents of this manuscript.

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40257_2018_414_MOESM1_ESM.xlsx

Supplementary table 1: In a pooled analysis of 1406 patient samples from 10 recent melanoma genomics studies using cBioPortal, 36 different KIT mutations were found. 18 of the 36 were rated “oncogenic” or “likely oncogenic” due to experimentally supported or predicted gain-of-function changes of the KIT protein. Additionally, 4 of 36 KIT mutations (K642E, V559A, L576P, W557R) in melanoma are recurrent mutations found in large patient cohorts of other cancers, supporting the critical role of KIT signaling in oncogenesis beyond melanoma. (XLSX 21 kb)

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Meng, D., Carvajal, R.D. KIT as an Oncogenic Driver in Melanoma: An Update on Clinical Development. Am J Clin Dermatol 20, 315–323 (2019). https://doi.org/10.1007/s40257-018-0414-1

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