PDF(Pubmed)
Abstract：
Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i\'s) in combination with chemotherapy have shown promising results in preclinical studies but have displayed minimal efficacy with substantial toxicity in clinical trials. To explore combinatorial strategies that can overcome these limitations, we perform an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identify thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a determinant of CHK1i sensitivity. We establish a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR inhibitor auranofin, an approved anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, we show a pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.
摘要：
检查点激酶1（CHK1）对于复制应激（RS）下的细胞存活至关重要。CHK1抑制剂（CHK1i）联合化疗在临床前研究中显示出了有希望的结果，但在临床试验中显示出最小的疗效和实质性的毒性。为了探索可以克服这些限制的组合策略，我们在非小细胞肺癌（NSCLC）细胞系中进行无偏高通量筛选，并鉴定硫氧还蛋白1（Trx1），哺乳动物抗氧化系统的主要组成部分，作为CHK1i灵敏度的决定因素。我们建立了RRM1的氧化还原循环的作用，RRM1是核糖核苷酸还原酶（RNR）的较大亚基，以及这种Trx1介导的CHK1i敏感性中脱氧核苷酸池的消耗。Further,TrxR抑制剂金诺芬，一种被批准的抗类风湿性关节炎药物,显示了通过脱氧核苷酸池的中断与CHK1i的协同相互作用。一起,我们展示了一种依赖于Trx系统与哺乳动物RNR活性之间的氧化还原调节联系的治疗NSCLC的药物组合.
