title: Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma.
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.
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.|Hospital Universitario 12 de Octubre, Complutense School of Medicine, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Martinez-Lopez
authors.affiliation: Karyopharm Therapeutics Inc, Newton, MA.
authors.forename: William
authors.initials: W
authors.lastname: Senapedis
authors.affiliation: Myeloma Unit, Division of Hematology, University of Turin, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Oliva
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Rajya
authors.initials: R
authors.lastname: Lakshmi Bandi
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Amodio
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Szalat
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Gulla
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Mehmet K
authors.initials: MK
authors.lastname: Samur
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.|CREA Laboratory, Department of Medical Oncology, ASST Spedali Civili di Brescia, Brescia, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Roccaro
authors.affiliation: Hospital Universitario 12 de Octubre, Complutense School of Medicine, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Linares
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.|Department of Medicine (DiMI), University of Genoa, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cea
authors.affiliation: Karyopharm Therapeutics Inc, Newton, MA.
authors.forename: Erkan
authors.initials: E
authors.lastname: Baloglu
authors.affiliation: Karyopharm Therapeutics Inc, Newton, MA.
authors.forename: Christian
authors.initials: C
authors.lastname: Argueta
authors.affiliation: Karyopharm Therapeutics Inc, Newton, MA.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
authors.affiliation: Karyopharm Therapeutics Inc, Newton, MA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Barnett Institute, Northeastern University, Boston, MA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Liu
authors.affiliation: Broad Institute, Cambridge, MA; and.
authors.forename: Monica
authors.initials: M
authors.lastname: Schenone
authors.affiliation: Barnett Institute, Northeastern University, Boston, MA.
authors.forename: Shiaw-Lin
authors.initials: SL
authors.lastname: Wu
authors.affiliation: Barnett Institute, Northeastern University, Boston, MA.
authors.forename: Barry
authors.initials: B
authors.lastname: Karger
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.|VA Boston Healthcare System, Boston, MA.
authors.forename: Rao
authors.initials: R
authors.lastname: Prabhala
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.|VA Boston Healthcare System, Boston, MA.
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002883:Chromosomes, Human, Pair 14; D002894:Chromosomes, Human, Pair 4; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D061251:Primary Cell Culture; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014178:Translocation, Genetic; D023041:Xenograft Model Antitumor Assays; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C116367:PAK4 protein, human; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D054462:p21-Activated Kinases; D020169:Caspases