Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Division of Translational Genomics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
Sci Adv. 2021 May 21;7(21). doi: 10.1126/sciadv.abf0197. Print 2021 May.
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.
细胞分裂周期蛋白 7（CDC7）是一种丝氨酸/苏氨酸激酶，在 DNA 复制中发挥重要作用。我们开发了一种高度特异性的 CDC7 抑制剂 TAK-931，作为一种临床癌症治疗药物。本研究旨在确定 TAK-931 的潜在联合伙伴，以指导其临床开发策略。无偏见的高通量化学筛选显示，观察到的协同增殖抑制作用最强的组合是 DNA 损伤药物与 TAK-931 的组合。功能磷酸蛋白质组学分析表明，TAK-931 抑制同源重组修复活性，延迟双链断裂的恢复，并导致组合中 DNA 损伤的积累。全基因组小干扰 RNA 文库筛选鉴定了敏感性调节分子，这些分子提出了组合的实验预测的靶癌症类型，包括胰腺癌、食管癌、卵巢癌和乳腺癌。在相应的原发性异种移植模型中，临床前证实了联合治疗在这些癌症类型中的疗效。因此，我们的研究结果将有助于指导 TAK-931 的未来临床策略。
