WEE1和CHEK1(CHK1)激酶是G2/M细胞周期检查点和DNA损伤应答途径的关键调节因子。WEE1抑制剂AZD1775和CHK1抑制剂SRA737正在进行各种癌症的临床试验,但没有在前列腺癌中检查过,特别是去势抵抗(CRPC)和神经内分泌前列腺癌(NEPC)。我们的数据表明在CRPC/NEPC细胞系和患者样品中WEE1和CHK1表达升高。AZD1775导致快速和有效的细胞杀伤,在不同的前列腺癌细胞系中具有相当的IC50,而SRA737显示时间依赖性进行性细胞杀伤,IC50差异为10至20倍。值得注意的是,它们的组合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的转基因小鼠模型中,两种药物单独或联合抑制肿瘤生长,总生存率提高,并降低了远处转移的发生率,SRA737具有显着的单剂抗癌活性。机械上,SRA737通过阻断AZD1775诱导的前列腺癌细胞中CHK1的反馈激活与AZD1775协同作用,导致有丝分裂进入和DNA损伤积累增加。总之,这项临床前研究表明,CHK1抑制剂SRA737单独使用及其与AZD1775的联合使用为CRPC和NEPC提供了潜在的有效治疗方法.
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.