Inactivation of the Kinase Domain of CDK10 Prevents Tumor Growth in a Preclinical Model of Colorectal Cancer, and Is Accompanied by Downregulation of Bcl-2

• Published in: Molecular cancer therapeutics Vol. 16; no. 10; pp. 2292 - 2303
• Main Authors: Weiswald, Louis-Bastien, Hasan, Mohammad R, Wong, John C T, Pasiliao, Clarissa C, Rahman, Mahbuba, Ren, Jianhua, Yin, Yaling, Gusscott, Samuel, Vacher, Sophie, Weng, Andrew P, Kennecke, Hagen F, Bièche, Ivan, Schaeffer, David F, Yapp, Donald T, Tai, Isabella T
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.10.2017
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Bcl-2 protein; Biomarkers; Biomarkers, Tumor - genetics; Biotechnology; Cancer; Cdc2 protein; Cell Line, Tumor; Cell Proliferation - drug effects; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Cyclin-dependent kinase 10; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - chemistry; Cyclin-Dependent Kinases - genetics; Deactivation; Defective mutant; Gene Expression Regulation, Neoplastic - drug effects; Humans; Inactivation; Kinases; Mice; Pathogenesis; Protein Domains - drug effects; Proto-Oncogene Proteins c-bcl-2 - genetics; siRNA; Tissues; Tumor cell lines; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-16-0666

Cyclin-dependent kinase 10 (CDK10), a CDC2-related kinase, is highly expressed in colorectal cancer. Its role in the pathogenesis of colorectal cancer is unknown. This study examines the function of CDK10 in colorectal cancer, and demonstrates its role in suppressing apoptosis and in promoting tumor growth and Modulation of CDK10 expression in colorectal cancer cell lines demonstrates that CDK10 promotes cell growth, reduces chemosensitivity and inhibits apoptosis by upregulating the expression of Bcl-2. This effect appears to depend on its kinase activity, as kinase-defective mutant colorectal cancer cell lines have an exaggerated apoptotic response and reduced proliferative capacity. , inhibiting CDK10 in colorectal cancer following intratumoral injections of lentivirus-mediated CDK10 siRNA in a patient-derived xenograft mouse model demonstrated its efficacy in suppressing tumor growth. Furthermore, using a tissue microarray of human colorectal cancer tissues, the potential for CDK10 to be a prognostic biomarker in colorectal cancer was explored. In tumors of individuals with colorectal cancer, high expression of CDK10 correlates with earlier relapse and shorter overall survival. The findings of this study indicate that CDK10 plays a role in the pathogenesis in colorectal cancer and may be a potential therapeutic target for treatment. .