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.

Molecular Pathways: Emergence of Protein Kinase CK2 (CSNK2) as a Potential Target to Inhibit Survival and DNA Damage Response and Repair Pathways in Cancer Cells

“…Antiproliferative activity was 23% to 38% higher than Bliss additivity when CX-4945 was added to cells after treatment with gemcitabine or cisplatin. These treatments were also accompanied by decreased phosphorylation of the CSNK2 substrates XRCC1 and MDC1 and accumulation of single-stranded and double-stranded DNA breaks (32). These data are in agreement with the observations of CSNK2 localizing to the nucleus in response to DSBs and for the role of CSNK2 in the DDR and DNA repair mechanisms (20,25,33,34).…”

Prediction Value of XRCC 1 Gene Polymorphism on the Survival of Ovarian Cancer Treated by Adjuvant Chemotherapy

“…However, the evidence of DNA repair gene on ovarian cancer patients with adjuvant chemotherapy in lacking. Several experimental studies reported the association between XRCC1 gene polymorphism and ovarian cancer risk, and the results are conflicting (Jakubowska et al, 2010;Siddiqui-Jain et al, 2012). Two studies conducted in Korea and Russian reported the association of XRCC1 Arg194Trp and XRCC1Arg399Gln gene polymorphisms with survival of ovarian cancer with chemotherapy (Kim et al, 2009;Khrunin et al, 2010).…”

Predictive Value of XRCC1 and XRCC3 Gene Polymorphisms for Risk of Ovarian Cancer Death After Chemotherapy

“…However, the evidence of DNA repair gene on ovarian cancer in lacking. Only several experimental studies reported the association between XRCC1 gene polymorphism and ovarian cancer risk, and the results are conflicting (Jakubowska et al, 2010;Kudo et al, 2012;Siddiqui-Jain et al, 2012;). A study reported inactivation of XRCC1 could influence the effect of platinum-based chemotherapeutics in the clinical setting.…”