Cancer cells develop protective adaptations against oxidative DNA damage, providing a strong rationale for targeting DNA repair proteins. There has been a high degree of recent interest in inhibiting the mammalian Nudix pyrophosphatase MutT Homolog 1 (MTH1). MTH1 degrades 8-oxo-dGTP, thus limiting its incorporation into genomic DNA. MTH1 inhibition has variously been shown to induce genomic 8-oxo-dG elevation, genotoxic strand breaks in p53-functional cells, and tumor-inhibitory outcomes. Genomically incorporated 8-oxo-dG is excised by the base excision repair enzyme, 8-oxo-dG glycosylase 1 (OGG1). Thus, OGG1 inhibitors have been developed with the idea that their combination with MTH1 inhibitors will have anti-tumor effects by increasing genomic oxidative DNA damage. However, contradictory to this idea, we found that human lung adenocarcinoma with low OGG1 and MTH1 were robustly represented in patient datasets. Furthermore, OGG1 co-depletion mitigated the extent of DNA strand breaks and cellular senescence in MTH1-depleted p53-wildtype lung adenocarcinoma cells. Similarly, shMTH1-transduced cells were less sensitive to the OGG1 inhibitor, SU0268, than shGFP-transduced counterparts. Although the dual OGG1/MTH1 inhibitor, SU0383, induced greater cytotoxicity than equivalent combined or single doses of its parent scaffold MTH1 and OGG1 inhibitors, IACS-4759 and SU0268, this effect was only observed at the highest concentration assessed. Collectively, using both genetic depletion as well as small molecule inhibitors, our findings suggest that OGG1/MTH1 co-inhibition is unlikely to yield significant tumor-suppressive benefit. Instead such co-inhibition may exert tumor-protective effects by preventing base excision repair-induced DNA nicks and p53 induction, thus potentially conferring a survival advantage to the treated tumors.

癌细胞针对氧化性DNA损伤产生保护性适应，为靶向DNA修复蛋白提供了强有力的依据。在抑制哺乳动物的Nudix焦磷酸酶MutT同源物1（MTH1）方面，近来引起了高度关注。MTH1降解8-oxo-dGTP，从而限制了其掺入基因组DNA中的能力。MTH1抑制已被证明可诱导基因组8-oxo-dG升高，p53功能细胞的遗传毒性链断裂和肿瘤抑制结果。通过碱基切除修复酶8-oxo-dG糖基化酶1（OGG1）切除基因组并入的8-oxo-dG。因此，已经开发出OGG1抑制剂，其思想是它们与MTH1抑制剂的组合将通过增加基因组氧化DNA损伤而具有抗肿瘤作用。但是，与此想法相反，OGG1和MTH1在患者数据集中被可靠地表示。此外，OGG1共耗竭减轻了MTH1耗竭的p53野生型肺腺癌细胞中DNA链断裂和细胞衰老的程度。同样，shMTH1转导的细胞对OGG1抑制剂SU0268的敏感性低于shGFP转导的对应物。尽管双重OGG1 / MTH1抑制剂SU0383比其母体支架MTH1和OGG1抑制剂IACS-4759和SU0268的等效组合或单剂量诱导的细胞毒性更大，但仅在评估的最高浓度下观察到了这种作用。总的来说，同时使用遗传耗竭和小分子抑制剂，我们的发现表明OGG1 / MTH1共抑制不太可能产生显着的肿瘤抑制益处。