// Batool Shannan 1, 2 , Andrea Watters 1 , Quan Chen 1 , Stefan Mollin 3 , Markus Dörr 3 , Eric Meggers 3 , Xiaowei Xu 4 , Phyllis A. Gimotty 5 , Michela Perego 1 , Ling Li 1 , Joseph Benci 1 , Clemens Krepler 1 , Patricia Brafford 1 , Jie Zhang 6 , Zhi Wei 6 , Gao Zhang 1 , Qin Liu 1 , Xiangfan Yin 1 , Katherine L. Nathanson 4 , Meenhard Herlyn 1, * , Adina Vultur 1, * 1 Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA 2 Department of Dermatology, University Hospital Essen, Essen, Germany 3 Department of Chemistry, University of Marburg, Marburg, Germany 4 Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 5 Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA 6 Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA * Co-senior authors Correspondence to: Adina Vultur, email: avultur@wistar.org Keywords: melanoma, PIM kinases, SGI-1776, organometallics, therapy Received: October 04, 2015 Accepted: June 06, 2016 Published: July 19, 2016 ABSTRACT Therapeutic strategies for the treatment of metastatic melanoma show encouraging results in the clinic; however, not all patients respond equally and tumor resistance still poses a challenge. To identify novel therapeutic targets for melanoma, we screened a panel of structurally diverse organometallic inhibitors against human-derived normal and melanoma cells. We observed that a compound that targets PIM kinases (a family of Ser/Thr kinases) preferentially inhibited melanoma cell proliferation, invasion, and viability in adherent and three-dimensional (3D) melanoma models. Assessment of tumor tissue from melanoma patients showed that PIM kinases are expressed in pre- and post-treatment tumors, suggesting PIM kinases as promising targets in the clinic. Using knockdown studies, we showed that PIM1 contributes to melanoma cell proliferation and tumor growth in vivo ; however, the presence of PIM2 and PIM3 could also influence the outcome. The inhibition of all PIM isoforms using SGI-1776 (a clinically-available PIM inhibitor) reduced melanoma proliferation and survival in preclinical models of melanoma. This was potentiated in the presence of the BRAF inhibitor PLX4720 and in the presence of PI3K inhibitors. Our findings suggest that PIM inhibitors provide promising additions to the targeted therapies available to melanoma patients.
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