Abstract
Abstract Background: Cell division cycle 7 (CDC7) is a serine/threonine kinase, which plays important roles in initiation of DNA replication. We developed a CDC7-selective inhibitor, TAK-931, designed to inhibit CDC7 activity in a time-dependent and ATP-competitive manner. In this study, we aimed to identify potential combination partners for TAK-931 to guide clinical combination strategies. Methods: In vitro combination studies of various agents with TAK-931 were carried out in COLO205, A549, SW620, SW48, H460, and HCT116 cancer cells using a fully automated system for assay execution and data analysis (Double Agent studies). Agents tested in combination with TAK-931 included: DNA damaging agents, tubulin binders, mitosis inhibitors, cell signaling modulators, proteasome inhibitors, and other targeted agents with significant single-agent activity against these cell lines. Treated stable isotope labeling using amino acids in cell culture (SILAC)-labeled H460 cells were subjected to quantitative mass spectrometry. In vivo combination studies of TAK-931 using DNA damaging agents or IR were conducted in multiple human xenograft models including patient-derived xenograft models (PDXs). Results: The Double Agent studies revealed that DNA damaging agents, such as topoisomerase inhibitors and platinum compounds, had the highest occurrence of synergistic antiproliferative effects in combination with TAK-931. In the phosphoproteomics analysis, gene ontology (GO) enrichment analysis revealed that DNA repair (p<0.01) and double-strand break (DSB) repair (p<0.01) were significantly enriched in the combination-treated cells with irradiation and TAK-931 (IR+TAK-931) compared with the untreated cells after 24 hours, whereas the enrichment of these pathways was not observed in the IR-treated cells. The functional analysis demonstrated that TAK-931 prolonged IR-induced 53BP1 foci formation (a DSB index), suppressed homologous recombination repair (HRR) activities, and hyperactivated DNA-damage response (DDR) pathways. These results suggest that TAK-931 could suppress DNA repair activity to enhance the biological activity of the DNA damaging agents for antiproliferation in cancer cells. Consistent with our hypothesis from in vitro studies, in vivo combination treatments of TAK-931 with DNA damaging agents, such as platinum compounds, topoisomerase inhibitors, and IR, also enhanced antitumor activities in multiple human xenograft models, including PDXs. Conclusions: Our findings suggest that chemotherapeutic drugs of DNA damaging agents could be potential candidates for combination with TAK-931 to expand its activity. Citation Format: Kenichi Iwai, Kurt Eng, Tadahiro Nambu, Jie Yu, Masamitsu Gotou, Sakiyo Tsukamoto, Saomi Murai, Shun-Ichiro Kageyama, Yukie Kashima, Susumu Kobayashi, Akihiro Ohashi. Potential combination partners for a novel CDC7-selective Inhibitor, TAK-931 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A093. doi:10.1158/1535-7163.TARG-19-A093
Published Version
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