Wang Qiming, Chao Yapeng, Chen Yuzhou, Zheng Wenxiao, Demanelis Kathryn, Liu Yu, Connelly Jaclyn, Wang Hong
University of Pittsburgh School of Medicine.
University of Pittsburgh Cancer Institute.
Res Sq. 2023 Nov 8:rs.3.rs-3564450. doi: 10.21203/rs.3.rs-3564450/v1.
WEE1 and CHEK1 (CHK1) kinases are critical regulators of the G2/M cell cycle checkpoint and DNA damage response pathways. The WEE1 inhibitor AZD1775 and the CHK1 inhibitor SRA737 are in clinical trials for various cancers, but have not been examined in prostate cancer, particularly castration-resistant (CRPC) and neuroendocrine prostate cancers (NEPC). Our data demonstrated elevated WEE1 and CHK1 expressions in CRPC/NEPC cell lines and patient samples. AZD1775 resulted in rapid and potent cell killing with comparable IC50s across different prostate cancer cell lines, while SRA737 displayed time-dependent progressive cell killing with 10- to 20-fold differences in IC50s. Notably, their combination synergistically reduced the viability of all CRPC cell lines and tumor spheroids in a concentration- and time-dependent manner. Importantly, in a transgenic mouse model of NEPC, both agents alone or in combination suppressed tumor growth, improved overall survival, and reduced the incidence of distant metastases, with SRA737 exhibiting remarkable single agent anticancer activity. Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC.
WEE1激酶和CHEK1（CHK1）激酶是G2/M细胞周期检查点和DNA损伤反应途径的关键调节因子。WEE1抑制剂AZD1775和CHK1抑制剂SRA737正在针对多种癌症进行临床试验，但尚未在前列腺癌中进行研究，尤其是去势抵抗性（CRPC）前列腺癌和神经内分泌前列腺癌（NEPC）。我们的数据表明，CRPC/NEPC细胞系和患者样本中WEE1和CHK1的表达升高。AZD1775能快速有效地杀死细胞，在不同前列腺癌细胞系中的半数抑制浓度（IC50）相当，而SRA737则表现出时间依赖性的渐进性细胞杀伤作用，其IC50相差10至20倍。值得注意的是，它们的联合使用以浓度和时间依赖性方式协同降低了所有CRPC细胞系和肿瘤球体的活力。重要的是，在NEPC转基因小鼠模型中，单独使用或联合使用这两种药物均能抑制肿瘤生长、提高总生存率并降低远处转移的发生率，其中SRA737表现出显著的单药抗癌活性。从机制上讲，SRA737与AZD1775协同作用，通过阻断AZD1775诱导的前列腺癌细胞中CHK1的反馈激活，导致有丝分裂进入增加和DNA损伤积累。总之，这项临床前研究表明，CHK1抑制剂SRA737单独使用及其与AZD1775联合使用为CRPC和NEPC提供了潜在的有效治疗方法。
