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 HerlynAdina Vultur

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)54897-54912
Number of pages16
JournalOncotarget
Volume7
Issue number34
DOIs
StatePublished - 2016

All Science Journal Classification (ASJC) codes

  • Oncology

Keywords

  • Melanoma
  • Organometallics
  • PIM kinases
  • SGI-1776
  • Therapy

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