Abstract
Dysregulated oncogenic serine/threonine kinases play a pathological role in diverse forms of malignancies, including multiple myeloma (MM), and thus represent potential therapeutic targets. Here, we evaluated the biological and functional role of p21-activated kinase 4 (PAK4) and its potential as a new target in MM for clinical applications. PAK4 promoted MM cell growth and survival via activation of MM survival signaling pathways, including the MEK-extracellular signal-regulated kinase pathway. Furthermore, treatment with orally bioavailable PAK4 allosteric modulator (KPT-9274) significantly impacted MM cell growth and survival in a large panel of MM cell lines and primary MM cells alone and in the presence of bone marrow microenvironment. Intriguingly, we have identified FGFR3 as a novel binding partner of PAK4 and observed significant activity of KPT-9274 against t(4;14)-positive MM cells. This set of data supports PAK4 as an oncogene in myeloma and provide the rationale for the clinical evaluation of PAK4 modulator in myeloma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, Non-U.S. Gov't
MeSH terms
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Allosteric Regulation
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Animals
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Apoptosis / drug effects
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / enzymology
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Bone Marrow Cells / pathology
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Caspases / genetics
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Caspases / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Chromosomes, Human, Pair 14
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Chromosomes, Human, Pair 4
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Gene Expression Regulation, Neoplastic*
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Humans
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / enzymology
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Leukocytes, Mononuclear / pathology
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Mice
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Mice, Nude
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Molecular Targeted Therapy
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / enzymology
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Multiple Myeloma / genetics*
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Multiple Myeloma / pathology
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Primary Cell Culture
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Protein Binding
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Protein Kinase Inhibitors / pharmacology*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Receptor, Fibroblast Growth Factor, Type 3 / genetics*
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Receptor, Fibroblast Growth Factor, Type 3 / metabolism
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Signal Transduction
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Translocation, Genetic
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Xenograft Model Antitumor Assays
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p21-Activated Kinases / antagonists & inhibitors
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p21-Activated Kinases / genetics*
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p21-Activated Kinases / metabolism
Substances
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Protein Kinase Inhibitors
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RNA, Small Interfering
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PAK4 protein, human
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FGFR3 protein, human
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Receptor, Fibroblast Growth Factor, Type 3
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p21-Activated Kinases
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Caspases