Abstract 1127: KIT/D816V induces SRC-mediated tyrosine phosphorylation of MITF and altered transcription program in melanoma
Phung B., Kazi JU., Lundby A., Bergsteinsdottir K., Sun J., Goding CR., Jönsson G., Olsen JV., Steingrímsson E., Rönnstrand L.
Abstract The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KITD816V has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KITD816V induces tyrosine phosphorylation of the microphthalmia-associated transcription factor (MITF) through a triple protein complex formation between KIT, MITF and SRC family kinases. In turn, phosphorylated MITF activates target genes that are involved in melanoma proliferation, cell cycle progression, suppression of senescence, survival and invasion. By blocking the triple protein complex formation, thus preventing MITF phosphorylation, the cells become hypersensitive to SRC inhibitors. We have therefore delineated the mechanism behind the oncogenic effects of KITD816V in melanoma and provide a rationale for testing SRC family kinase inhibitors to treat KITD816V-transformed melanomas. Citation Format: Bengt Phung, Julhash U. Kazi, Alicia Lundby, Kristin Bergsteinsdottir, Jianmin Sun, Colin R. Goding, Göran Jönsson, Jesper V. Olsen, Eiríkur Steingrímsson, Lars Rönnstrand. KIT/D816V induces SRC-mediated tyrosine phosphorylation of MITF and altered transcription program in melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1127.