Abstract
Abstract Oncogenic RAS signaling is mediated by reactive oxygen species (ROS) signaling. However, oncogenic ROS also evoke tumor suppressive damage, necessitating adaptive redox protective mechanisms. We previously reported that MTH1, the main mammalian 8-oxodGTPase, comprises one such critical adaptation. High MTH1 expression significantly correlates with poor disease-free survival in several KRAS-driven tumors. We have shown in RAS-driven xenograft cancer models that MTH1 is critical for the maintenance of ROS-driven signaling and prevention of DNA damage-induced senescence. However, how MTH1 loss affects KRAS-driven spontaneous tumor formation is unknown. We focused on pancreatic ductal adenocarcinoma (PDAC) due to the high prevalence of driving oncogenic KRASG12D mutations, and the lack of MTH1 studies. Therefore, we depleted MTH1 via shRNA in MIA PacCa-2 and SU.86.86 cell lines and generated novel MTH1-null Pdx1Cre; LSL-KrasG12D/+; LSL-Trp53R172H/+ (KPC), Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) and corresponding MTH1-wildtype strains. We found MTH1 knockdown significantly reduced growth of KRAS-driven PDAC cells, and that germline MTH1 deficiency reduced tumor burden in the short latency PKT but not the long latency KPC animals. The PKT tumors exhibited higher overall 8-oxodGTPase activity and reduced total 8-oxo-dGTPase activity in the MTH1-deficient background, unlike KPC tumors. This finding suggests that in aggressive KRAS-driven tumors, redundant 8-oxodGTPase activity cannot compensate for MTH1 loss to prevent oncogenic stress-induced tumor suppression. Additionally, both MTH1-depleted PDAC cell lines and the smaller MTH1-null PKT tumors had decreased EGFR expression, suggesting MTH1 loss compromises this ROS-driven pathway. RNA-seq analysis revealed MTH1 deficiency altered MDSC gene expression in the PKT model, suggesting better anti-tumor response through improved immune infiltration in a typically immunologically cold tumor. Our results indicate MTH1 targeting could benefit aggressive PDAC stages. We further show PDAC tumors possess redundancy in MTH1 8-oxodGTPase function, which needs to be better understood in order to therapeutically leverage current MTH1 inhibitors, which do not target this redundancy. Citation Format: Beatriz Mateo-Victoriano, Ling Zhang, Govindi J. Samaranayake, Cassie Due, Clara Troccoli, Julia Zaias, Nagaraj Nagathihalli, Michael VanSaun, Michael G. Mohsen, Eric T. Kool, Priyamvada Rai. Oxidation in the nucleotide pool as a novel targetable vulnerability in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4790.
