Oncotarget

Research Papers:

PIM kinases as therapeutic targets against advanced melanoma

Batool Shannan, Andrea Watters, Quan Chen, Stefan Mollin, Markus Dörr, Eric Meggers, Xiaowei Xu, Phyllis A. Gimotty, Michela Perego, Ling Li, Joseph Benci, Clemens Krepler, Patricia Brafford, Jie Zhang, Zhi Wei, Gao Zhang, Qin Liu, Xiangfan Yin, Katherine L. Nathanson, Meenhard Herlyn, Adina Vultur _

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Abstract

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

*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.

Author Information

Batool Shannan

Andrea Watters

Quan Chen

Stefan Mollin

Markus Dörr

Eric Meggers

Xiaowei Xu

Phyllis A. Gimotty

Michela Perego

Ling Li

Joseph Benci

Clemens Krepler

Patricia Brafford

Jie Zhang

Zhi Wei

Gao Zhang

Qin Liu

Xiangfan Yin

Katherine L. Nathanson

Meenhard Herlyn

Adina Vultur
Primary Contact  _


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