Department of Cancer Genetics and Genomics, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Division of Pediatric Oncology, Roswell Park Comprehensive Cancer Center, Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York.
Cancer Res Commun. 2022 Jun;2(6):471-482. doi: 10.1158/2767-9764.crc-22-0130. Epub 2022 Jun 20.
Ewing sarcoma is an aggressive childhood cancer for which treatment options remain limited and toxic. There is an urgent need for the identification of novel therapeutic strategies. Our group has recently shown that Ewing cells rely on the S-phase kinase CDC7 (DDK) to maintain replication rates and cell viability and that DDK inhibition causes an increase in the phosphorylation of CDK1 and a significant delay in mitotic entry. Here, we expand on our previous findings and show that DDK inhibitor-induced mitotic entry delay is dependent upon WEE1 kinase. Specifically, WEE1 phosphorylates CDK1 and prevents mitotic entry upon DDK inhibition due to the presence of under-replicated DNA, potentially limiting the cytotoxic effects of DDK inhibition. To overcome this, we combined the inhibition of DDK with the inhibition of WEE1 and found that this results in elevated levels of premature mitotic entry, mitotic catastrophe, and apoptosis. Importantly, we have found that DDK and WEE1 inhibitors display a synergistic relationship with regards to reducing cell viability of Ewing sarcoma cells. Interestingly, the cytotoxic nature of this combination can be suppressed by the inhibition of CDK1 or microtubule polymerization, indicating that mitotic progression is required to elicit the cytotoxic effects. This is the first study to display the potential of utilizing the combined inhibition of DDK and WEE1 for the treatment of cancer. We believe this will offer a potential therapeutic strategy for the treatment of Ewing sarcoma as well as other tumor types that display sensitivity to DDK inhibitors.
尤因肉瘤是一种侵袭性儿童癌症，其治疗选择仍然有限且有毒。迫切需要确定新的治疗策略。我们的小组最近表明，尤因细胞依赖 S 期激酶 CDC7（DDK）来维持复制率和细胞活力，并且 DDK 抑制导致 CDK1 的磷酸化增加，并且有丝分裂进入显著延迟。在这里，我们扩展了我们之前的发现，并表明 DDK 抑制剂诱导的有丝分裂进入延迟依赖于 WEE1 激酶。具体而言，WEE1 磷酸化 CDK1，并在 DDK 抑制后阻止有丝分裂进入，因为存在复制不足的 DNA，可能限制 DDK 抑制的细胞毒性作用。为了克服这一点，我们将 DDK 抑制与 WEE1 抑制相结合，发现这导致过早的有丝分裂进入、有丝分裂灾难和细胞凋亡水平升高。重要的是，我们发现 DDK 和 WEE1 抑制剂在降低尤因肉瘤细胞活力方面表现出协同关系。有趣的是，这种组合的细胞毒性性质可以通过抑制 CDK1 或微管聚合来抑制，表明有丝分裂进展是产生细胞毒性作用所必需的。这是第一项显示联合抑制 DDK 和 WEE1 治疗癌症潜力的研究。我们相信，这将为治疗尤因肉瘤以及其他对 DDK 抑制剂敏感的肿瘤类型提供一种潜在的治疗策略。
