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.
Highlights
DNA-targeted chemotherapeutics represent fundamental components of modern cancer therapy and are currently prescribed for multiple indications
Because CK2 is involved in multiple processes that regulate the sensitivity of cancer cells to such DNA-targeted anticancer drugs [10, 13, 16], we asked whether combining CX-4945 with gemcitabine or cisplatin can improve the effectiveness of these chemotherapeutics
To ensure inhibition of CK2 signaling throughout the experiment, cells were pretreated with CX-4945 4 hours before addition of either gemcitabine or cisplatin, and the presence of CX-4945 was maintained throughout the treatment period
Summary
DNA-targeted chemotherapeutics represent fundamental components of modern cancer therapy and are currently prescribed for multiple indications. These agents target the DNA of tumor cells and can activate one or more DNA repair response mechanisms, potentially leading to the development of drug resistance [1]. An emerging strategy to boost the effectiveness of these drugs is to combine them with inhibitors of corresponding DNA repair response mechanisms [1, 2]. Methods currently subject to clinical investigation include inhibitors of the Authors' Affiliations: 1Cylene Pharmaceuticals, San Diego, California; and 2Translational Genomics Research Institute, Phoenix, Arizona. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/). The editor-in-chief of Molecular Cancer Therapeutics is a coauthor of this paper. In keeping with the AACR's Editorial Policy, a member of the AACR's Publications Committee had the paper reviewed independently of the journal's editorial process and made the decision whether to accept the paper
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