Compound Screen Identifies Pim Kinases As Therapeutic Targets For Melanoma

Current treatments against malignant melanoma, including the use of small molecule inhibitors, are displaying encouraging results in the clinic. However, tumor resistance develops even for patients who initially respond favorably. To identify novel drug targets and compounds with anti-melanoma activity, we screened a panel of genetically distinct human-derived metastatic melanoma cell lines against structurally diverse organometallic kinase inhibitors. We observed a compound that preferentially inhibits melanoma cell proliferation compared to normal primary fibroblasts and melanocytes in adherent and three-dimensional (3D) cultures. We further showed that this compound (SM200) is pro-apoptotic and anti-invasive in 3D melanoma cell cultures. A kinome screen to identify the targets responsible for the anti-melanoma effects of SM200 revealed PIM kinases to be highly inhibited. PIM1 knockdown studies to validate this target in human metastatic melanoma indicate that PIM1 contributes to melanoma growth in 3D culture and in a xenograft model. We then evaluated the clinically available PIM kinase inhibitor SGI-1776 in our melanoma models and observed reduced cell proliferation in 2D, 3D, and in vivo melanoma models (as seen for SM200) suggesting an important role for PIM kinases in melanoma pathobiology. Taken together, our findings suggest that PIM kinases are valid targets for melanoma and PIM kinase inhibitors could enhance the effects of current therapies in the clinic. Citation Format: Adina M. Vultur, Batool Shannan, Quan Chen, Andrea Watters, Stefan Mollin, Eric Meggers, Clemens Krepler, Michela Perego, Ling Li, Phyllis A. Gimotty, Xiaowei Xu, Meenhard Herlyn. Compound screen identifies PIM kinases as therapeutic targets for melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 687. doi:10.1158/1538-7445.AM2015-687