Pathophysiological significance and therapeutic targeting of germinal center kinase in diffuse large B-cell lymphoma

Blood. 2016 Jul 14;128(2):239-48. doi: 10.1182/blood-2016-02-696856.

Julie Marie Matthews ¹, Shruti Bhatt ², Matthew P Patricelli ³, Tyzoon K Nomanbhoy ³, Xiaoyu Jiang ⁴, Yasodha Natkunam ⁵, Andrew J Gentles ⁶, Ezequiel Martinez ⁷, Daxing Zhu ⁴, Jennifer Rose Chapman ⁸, Elena Cortizas ⁹, Ragini Shyam ¹⁰, Shideh Chinichian ¹⁰, Ranjana Advani ¹⁰, Li Tan ¹¹, Jianming Zhang ¹¹, Hwan Geun Choi ¹², Robert Tibshirani ¹³, Sara J Buhrlage ¹², Dita Gratzinger ⁵, Ramiro Verdun ⁹, Nathanael S Gray ¹¹, Izidore S Lossos ¹⁴

Affiliations

1 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;
2 Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL;
3 ActivX Biosciences, Inc, La Jolla, CA;
4 Division of Hematology-Oncology, Department of Medicine, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL;
5 Department of Pathology and.
6 Center for Cancer Systems Biology, Stanford University School of Medicine, Stanford, CA; Department of Radiology, Stanford University, Stanford, CA;
7 Department of Cancer Biology.
8 Department of Pathology, Sylvester Comprehensive Cancer Center, and.
9 Division of Gerontology and Geriatric Medicine, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL;
10 Oncology Division, Stanford University School of Medicine, Stanford, CA;
11 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA; and.
12 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA; and.
13 Department of Health Research and Policy, and Department of Statistics, Stanford University, Stanford, CA.
14 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.

PMID: 27151888 DOI: 10.1182/blood-2016-02-696856

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.

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