CK2 inhibitor CX-4945 suppresses DNA repair response triggered by DNA-targeted anticancer drugs and augments efficacy: mechanistic rationale for drug combination therapy.

Abstract

Drug combination therapies are commonly used for the treatment of cancers to increase therapeutic efficacy, reduce toxicity, and decrease the incidence of drug resistance. Although drug combination therapies were originally devised primarily by empirical methods, the increased understanding of drug mechanisms and the pathways they modulate provides a unique opportunity to design combinations that are based on mechanistic rationale. We have identified protein kinase CK2 as a promising therapeutic target for combination therapy, because CK2 regulates not just one but many oncogenic pathways and processes that play important roles in drug resistance, including DNA repair, epidermal growth factor receptor signaling, PI3K/AKT/mTOR signaling, Hsp90 machinery activity, hypoxia, and interleukin-6 expression. In this article, we show that CX-4945, a clinical stage selective small molecule inhibitor of CK2, blocks the DNA repair response induced by gemcitabine and cisplatin and synergizes with these agents in models of ovarian cancer. Mechanistic studies show that the enhanced activity is a result of inactivation of XRCC1 and MDC1, two mediator/adaptor proteins that are essential for DNA repair and that require phosphorylation by CK2 for their function. These data position CK2 as a valid pharmacologic target for intelligent drug combinations and support the evaluation of CX-4945 in combination with gemcitabine and platinum-based chemotherapeutics in the clinical setting.

• Authors: Adam Siddiqui-Jain, Joshua Bliesath, Diwata Macalino, Mayuko Omori, Nanni Huser, Nicole Streiner, Caroline B Ho, Kenna Anderes, Chris Proffitt, Sean E O'Brien, John K C Lim, Daniel D Von Hoff, David M Ryckman, William G Rice, Denis Drygin
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 4 Pg. 994-1005 (Apr 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22267551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• Naphthyridines
• Phenazines
• silmitasertib
• Checkpoint Kinase 2
• CHEK2 protein, human
• Casein Kinase II
• Chek2 protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Casein Kinase II (antagonists & inhibitors)
• Cell Line, Tumor
• Checkpoint Kinase 2
• DNA Repair (drug effects)
• Drug Synergism
• Female
• Humans
• Mice
• Naphthyridines (administration & dosage, pharmacology)
• Neoplasms (drug therapy, genetics)
• Ovarian Neoplasms (drug therapy, enzymology, genetics)
• Phenazines
• Phosphorylation
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Random Allocation
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays