title: PIM kinases as therapeutic targets against advanced melanoma.
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.
authors.affiliation: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.|Department of Dermatology, University Hospital Essen, Essen, Germany.
authors.forename: Batool
authors.initials: B
authors.lastname: Shannan
authors.affiliation: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Watters
authors.affiliation: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Chemistry, University of Marburg, Marburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mollin
authors.affiliation: Department of Chemistry, University of Marburg, Marburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Dörr
authors.affiliation: Department of Chemistry, University of Marburg, Marburg, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Meggers
authors.affiliation: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Gimotty
authors.affiliation: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Michela
authors.initials: M
authors.lastname: Perego
authors.affiliation: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Benci
authors.affiliation: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Clemens
authors.initials: C
authors.lastname: Krepler
authors.affiliation: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Brafford
authors.affiliation: Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Gao
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Xiangfan
authors.initials: X
authors.lastname: Yin
authors.affiliation: Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Adina
authors.initials: A
authors.lastname: Vultur
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology; D034622:RNA Interference; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D062367:ortho-Aminobenzoates / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: C578518:2-(1-(7-methyl-2-morpholin-4-yl-4-oxo-4H-pyrido(1,2-a)pyrimidin-9-yl)ethylamino)benzoic acid; D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D007211:Indoles; C548887:MK 2206; C490587:PIM2 protein, human; C528407:PLX 4720; D011518:Proto-Oncogene Proteins; D011724:Pyridazines; D011744:Pyrimidinones; C545188:SGI 1776; D013449:Sulfonamides; D062367:ortho-Aminobenzoates; C496634:PIM1 protein, human; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim
keywords: PIM kinases; SGI-1776; melanoma; organometallics; therapy