A CDC7 inhibitor sensitizes DNA-damaging chemotherapies by suppressing homologous recombination repair to delay DNA damage recovery

Abstract

Cell division cycle 7 (CDC7), a serine/threonine kinase, plays important roles in DNA replication. We developed a highly specific CDC7 inhibitor, TAK-931, as a clinical cancer therapeutic agent. This study aimed to identify the potential combination partners of TAK-931 for guiding its clinical development strategies. Unbiased high-throughput chemical screening revealed that the highest synergistic antiproliferative effects observed were the combinations of DNA-damaging agents with TAK-931. Functional phosphoproteomic analysis demonstrated that TAK-931 suppressed homologous recombination repair activity, delayed recovery from double-strand breaks, and led to accumulation of DNA damages in the combination. Whole-genome small interfering RNA library screening identified sensitivity-modulating molecules, which propose the experimentally predicted target cancer types for the combination, including pancreatic, esophageal, ovarian, and breast cancers. The efficacy of combination therapy in these cancer types was preclinically confirmed in the corresponding primary-derived xenograft models. Thus, our findings would be helpful to guide the future clinical strategies for TAK-931.

Germline ERCC excision repair 6 like 2 (ERCC6L2) mutations lead to impaired erythropoiesis and reshaping of the bone marrow microenvironment

“…Next, we performed differential gene expression and gene set enrichment analysis (GSEA) on ERCC6L2 ‐deficient erythroid‐committed HSPCs to examine the molecular pathways impacted by ERCC6L2‐ silencing. In all, 21 genes were significantly upregulated in both patient and ERCC6L2 ‐KD cells (Figure 4C ; p adj < 0.05, fold change >1.5), including genes involved in DNA damage recovery (cell division cycle 7 [ CDC7 ], 12 epithelial cell transforming 2 [ ECT2 ] 13 ) and regulation of erythropoiesis (hemogen [ HEMGN ] 14 , 15 ). Moreover, hierarchical clustering of differentially expressed genes showed that patient and KD cells clustered most closely together (Figure 4D ), suggesting that ERCC6L2 ‐deficiency drives a specific biological signature.…”

Identifying CDC7 as a synergistic target of chemotherapy in resistant small-cell lung cancer via CRISPR/Cas9 screening

“…Given the key role of CDC7 in the cell cycle and DNA synthesis [ 29 ], many inhibitors are being developed to serve as antitumor agents. Targeting CDC7 induces DNA replication stress and shows therapeutic effects when applied either alone [ 11 , 12 ] or in combination with other treatments [ 29 , 30 ].…”

“…Given the key role of CDC7 in the cell cycle and DNA synthesis [ 29 ], many inhibitors are being developed to serve as antitumor agents. Targeting CDC7 induces DNA replication stress and shows therapeutic effects when applied either alone [ 11 , 12 ] or in combination with other treatments [ 29 , 30 ]. Our results showed that a CDC7 inhibitor combined with chemotherapy can induce cell cycle arrest and apoptosis, but more evidence is needed to elucidate the mechanisms linking these two treatments.…”

WEE1 Inhibition Augments CDC7 (DDK) Inhibitor–induced Cell Death in Ewing Sarcoma by Forcing Premature Mitotic Entry and Mitotic Catastrophe

“…Therefore, we hypothesize that tumors with known origin activity alterations or a reliance on dormant origin usage are prime candidates for DDK + WEE1 inhibition. Work by others suggests that some types of pancreatic, esophageal, ovarian, and breast cancers may be vulnerable to DDKi (63), especially in combination with chemotherapeutic agents. This study did not look at potential synergy with Wee1i or utilize Ewing sarcoma models.…”