PIM kinases as therapeutic targets against advanced melanoma
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Batool Shannan1,2, Andrea Watters1, Quan Chen1, Stefan Mollin3, Markus Dörr3, Eric Meggers3, Xiaowei Xu4, Phyllis A. Gimotty5, Michela Perego1, Ling Li1, Joseph Benci1, Clemens Krepler1, Patricia Brafford1, Jie Zhang6, Zhi Wei6, Gao Zhang1, Qin Liu1, Xiangfan Yin1, Katherine L. Nathanson4, Meenhard Herlyn1,*, Adina Vultur1,*
1Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA
2Department of Dermatology, University Hospital Essen, Essen, Germany
3Department of Chemistry, University of Marburg, Marburg, Germany
4Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
5Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
6Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA
Adina Vultur, email: [email protected]
Keywords: melanoma, PIM kinases, SGI-1776, organometallics, therapy
Received: October 04, 2015 Accepted: June 06, 2016 Published: July 19, 2016
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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