title: Pyk2 promotes tumor progression in multiple myeloma.
abstract: Proline-rich tyrosine kinase 2 (Pyk2) is a member of the focal adhesion kinase family that has been recently linked to tumor development. However, its role in modulating multiple myeloma (MM) biology and disease progression remains unexplored. We first demonstrated that patients with MM present with higher expression of Pyk2 compared with healthy individuals. By using loss-of-function approaches, we found that Pyk2 inhibition led to reduction of MM tumor growth in vivo as well as decreased cell proliferation, cell-cycle progression, and adhesion ability in vitro. In turn, overexpression of Pyk2 promoted the malignant phenotype, substantiated by enhanced tumor growth and reduced survival. Mechanistically, inhibition of Pyk2 reduced activation of Wnt/β-catenin signaling by destabilizing β-catenin, leading to downregulation of c-Myc and Cyclin D1. Furthermore, treatment of MM cells with the FAK/Pyk2 inhibitor VS-4718 effectively inhibited MM cell growth both in vitro and in vivo. Collectively, our findings describe the tumor-promoting role of Pyk2 in MM, thus providing molecular evidence for a novel tyrosine kinase inhibitor as a new therapeutic option in MM.
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; The First People's Hospital of Yunnan Province, Department of Gastroenterology, Kunming, China;
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Michele
authors.initials: M
authors.lastname: Moschetta
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Daisy
authors.initials: D
authors.lastname: Huynh
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; Nanfang Hospital, Southern Medical University, Guangzhou, China; and.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishima
authors.affiliation: Verastem Inc., Cambridge, MA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Ring
authors.affiliation: Verastem Inc., Cambridge, MA.
authors.forename: Winnie F
authors.initials: WF
authors.lastname: Tam
authors.affiliation: Verastem Inc., Cambridge, MA.
authors.forename: Qunli
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Patricia
authors.initials: P
authors.lastname: Maiso
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Michaela
authors.initials: M
authors.lastname: Reagan
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Ilyas
authors.initials: I
authors.lastname: Sahin
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Salomon
authors.initials: S
authors.lastname: Manier
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Yosra
authors.initials: Y
authors.lastname: Aljawai
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Siobhan
authors.initials: S
authors.lastname: Glavey
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: Verastem Inc., Cambridge, MA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Pachter
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Roccaro
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008163:Luminescent Measurements; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D000631:Aminopyridines; C559284:PND 1186; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D049452:Green Fluorescent Proteins; D051418:Focal Adhesion Kinase 2