Abstract 2076: Low OGG1 protects against the DNA damage induced by MTH1 inhibition

Abstract

Increased metabolic activity of cancer cells due to uncontrolled proliferation, often leads to the accumulation of reactive oxygen species (ROS). High ROS can produce tumor-suppressive oxidative DNA damage either directly in the genome or through oxidation of deoxynucleotides that can then be incorporated into DNA. The human 8-oxoguanine glycosylase 1 (OGG1), a base excision repair (BER) enzyme, protects cells from the former by excising genomic 8-oxodG; MutT Homolog 1 (MTH1), the mammalian 8-oxodGTPase, protects cells from the latter by degrading 8-oxo-dGTP. There has been much interest in increasing oxidative DNA damage in tumors as a therapeutic option. Accordingly, inhibitors are being developed that can target both MTH1 and 8-oxodG glycosylase 1 (OGG1) with the speculation that this co-targeting will significantly increase tumor suppression efficiency. Our lab has shown that MTH1 inhibition leads to DNA strand breaks and tumor-suppressive effects in cancers characterized by high MTH1enzymatic activity. Here we assessed whether co-inhibition of OGG1 would provide benefits in tumor-suppressive effects over MTH1 inhibition alone. We first compared OGG1 and MTH1 expression in paired normal versus tumor tissue from lung adenocarcinoma patients and found that, unlike MTH1, OGG1 tends to remain within normal range in cancerous tissue. Similarly, TCGA lung adenocarcinoma patients show minimal OGG1 elevations and a positive correlation between OGG1 and MTH1 mRNA levels even when both are low. This data suggests that tumors with low OGG1 and MTH1 are robustly represented in the tumor continuum. We then co-depleted OGG1/MTH1 in the A549 lung cancer cell line and found this co-depletion led to lower DNA strand breaks and decreased cell senescence over those caused by MTH1 depletion alone. The shMTH1-transduced cells were less sensitive to SU0268, a potent OGG1 inhibitor compared to shGFP-transduced counterparts. We also treated A549 cells with SU0383, a dual OGG1/MTH1 inhibitor. The dual-inhibitor did not consistently increase cytotoxicity either with duration or dose of treatment beyond single inhibitors or combined single MTH1 and OGG1 inhibitors. In conclusion, our findings suggest that the co-inhibition of OGG1 with MTH1 does not produce enhanced therapeutic benefit in tumor cells, and could instead diminish the tumor-inhibitory effects of MTH1 inhibition that arise from induction of DNA strand breaks and p53-induced senescence. Citation Format: Laura Misiara Lincheta, Ling Zhang, Govindi Samaranayake, Nisha Sharma, Dao Nguyen, Yu-Ki Tahara, Eric Kool, Priyamvada Rai. Low OGG1 protects against the DNA damage induced by MTH1 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2076.