title: Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma.
abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, yet 40% to 50% of patients will eventually succumb to their disease, demonstrating a pressing need for novel therapeutic options. Gene expression profiling has identified messenger RNAs that lead to transformation, but critical events transforming cells are normally executed by kinases. Therefore, we hypothesized that previously unrecognized kinases may contribute to DLBCL pathogenesis. We performed the first comprehensive analysis of global kinase activity in DLBCL, to identify novel therapeutic targets, and discovered that germinal center kinase (GCK) was extensively activated. GCK RNA interference and small molecule inhibition induced cell-cycle arrest and apoptosis in DLBCL cell lines and primary tumors in vitro and decreased the tumor growth rate in vivo, resulting in a significantly extended lifespan of mice bearing DLBCL xenografts. GCK expression was also linked to adverse clinical outcome in a cohort of 151 primary DLBCL patients. These studies demonstrate, for the first time, that GCK is a molecular therapeutic target in DLBCL tumors and that inhibiting GCK may significantly extend DLBCL patient survival. Because the majority of DLBCL tumors (∼80%) exhibit activation of GCK, this therapy may be applicable to most patients.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL; Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL;
authors.forename: Julie Marie
authors.initials: JM
authors.lastname: Matthews
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL;
authors.forename: Shruti
authors.initials: S
authors.lastname: Bhatt
authors.affiliation: ActivX Biosciences, Inc, La Jolla, CA;
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Patricelli
authors.affiliation: ActivX Biosciences, Inc, La Jolla, CA;
authors.forename: Tyzoon K
authors.initials: TK
authors.lastname: Nomanbhoy
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL;
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Pathology and.
authors.forename: Yasodha
authors.initials: Y
authors.lastname: Natkunam
authors.affiliation: Center for Cancer Systems Biology, Stanford University School of Medicine, Stanford, CA; Department of Radiology, Stanford University, Stanford, CA;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gentles
authors.affiliation: Department of Cancer Biology.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Martinez
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL;
authors.forename: Daxing
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Pathology, Sylvester Comprehensive Cancer Center, and.
authors.forename: Jennifer Rose
authors.initials: JR
authors.lastname: Chapman
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL;
authors.forename: Elena
authors.initials: E
authors.lastname: Cortizas
authors.affiliation: Oncology Division, Stanford University School of Medicine, Stanford, CA;
authors.forename: Ragini
authors.initials: R
authors.lastname: Shyam
authors.affiliation: Oncology Division, Stanford University School of Medicine, Stanford, CA;
authors.forename: Shideh
authors.initials: S
authors.lastname: Chinichian
authors.affiliation: Oncology Division, Stanford University School of Medicine, Stanford, CA;
authors.forename: Ranjana
authors.initials: R
authors.lastname: Advani
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: Li
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.affiliation: Department of Health Research and Policy, and Department of Statistics, Stanford University, Stanford, CA.
authors.forename: Robert
authors.initials: R
authors.lastname: Tibshirani
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Buhrlage
authors.affiliation: Department of Pathology and.
authors.forename: Dita
authors.initials: D
authors.lastname: Gratzinger
authors.affiliation: Division of Gerontology and Geriatric Medicine, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL;
authors.forename: Ramiro
authors.initials: R
authors.lastname: Verdun
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA; and.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL; Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL; Department of Cancer Biology.
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
mesh_terms: D000818:Animals; D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D000081410:Germinal Center Kinases; D064593:Heterografts; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000208:ethnology* / Q000401:mortality / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009368:Neoplasm Transplantation; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*
chemical_list: D000081410:Germinal Center Kinases; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases