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.
Keywords:
PIM kinases; SGI-1776; melanoma; organometallics; therapy.
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Gene Expression Profiling / methods
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Heterocyclic Compounds, 3-Ring / administration & dosage
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Imidazoles / administration & dosage
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Imidazoles / pharmacology*
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Indoles / administration & dosage
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Indoles / pharmacology
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Melanoma / drug therapy*
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Melanoma / genetics
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Melanoma / metabolism
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Mice, Inbred NOD
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Mice, Knockout
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Mice, SCID
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-pim-1 / genetics
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Proto-Oncogene Proteins c-pim-1 / metabolism
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Pyridazines / administration & dosage
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Pyridazines / pharmacology*
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Pyrimidinones / administration & dosage
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Pyrimidinones / pharmacology
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RNA Interference
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Sulfonamides / administration & dosage
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Sulfonamides / pharmacology
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Tumor Burden / drug effects
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Tumor Burden / genetics
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Xenograft Model Antitumor Assays*
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ortho-Aminobenzoates / administration & dosage
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ortho-Aminobenzoates / pharmacology
Substances
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2-(1-(7-methyl-2-morpholin-4-yl-4-oxo-4H-pyrido(1,2-a)pyrimidin-9-yl)ethylamino)benzoic acid
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Heterocyclic Compounds, 3-Ring
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Imidazoles
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Indoles
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MK 2206
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PIM2 protein, human
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PLX 4720
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Proto-Oncogene Proteins
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Pyridazines
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Pyrimidinones
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SGI 1776
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Sulfonamides
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ortho-Aminobenzoates
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PIM1 protein, human
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PIM3 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-pim-1
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proto-oncogene proteins pim