Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition.
Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition.
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同源重组（HR）缺陷细胞，如缺乏BRCA1/2的细胞，对聚（adp -核糖）聚合酶（PARP）抑制非常敏感。然而，brca缺陷肿瘤仅占成人癌症的一小部分，这可能限制了PARP抑制剂单药治疗的疗效。我们之前的研究表明，细胞周期蛋白依赖性激酶（cdk）1磷酸化BRCA1，这是有效形成BRCA1病灶的必要事件。在这里，我们表明cdk1的耗尽或抑制会损害细胞通过HR修复DNA的能力。在小鼠肺腺癌模型中，联合抑制BRCA野生型癌细胞中的cdk1和PARP可减少集落形成，延缓人类肿瘤异种移植生长和肿瘤消退，延长生存期。抑制Cdk1不会使未转化的细胞或组织对PARP抑制敏感。由于cdk1活性降低会损害BRCA1功能和HR修复，因此cdk1抑制是一种合理的策略，可以将PARP抑制剂的效用扩大到brca精通的癌症人群。
Homologous recombination (HR)-defective cells, such as those lacking BRCA1/2, are hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition. However, BRCA-deficient tumors represent only a small fraction of adult cancers, potentially restricting the therapeutic utility of PARP inhibitor monotherapy. We previously showed that cyclin-dependent kinase (cdk)1 phosphorylates BRCA1, an event essential for efficient BRCA1 focus formation. Here, we show that cdk1 depletion or inhibition compromises the cellular capacity to repair DNA by HR. Combined cdk1 and PARP inhibition in BRCA wild-type cancer cells results in reduced colony formation, delayed human tumor xenograft growth and tumor regression with prolonged survival in a mouse lung adenocarcinoma model. Cdk1 inhibition did not sensitize non-transformed cells or tissues to PARP inhibition. Because reduced cdk1 activity impairs BRCA1 function and HR repair, cdk1 inhibition represents a plausible strategy for expanding the utility of PARP inhibitors to the BRCA-proficient cancer population.
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