Abstract 2967: The mammalian 8-oxo-dGTPase, MTH1, as a novel targetable vulnerability in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive KRAS-driven cancer that remains one of the most lethal of all human malignancies. Oncogenic KRAS relies on elevated reactive oxygen species (ROS) to support pro-tumorigenic signaling. However, these elevated ROS levels can also evoke tumor suppressive oxidative stress; thus KRAS-driven cancers must evolve protective redox adaptations to mitigate ROS-induced anti-tumor consequences. Here we report a unique adaptation centered on redox maintenance of nucleotide pool integrity, that supports aggressive PDAC tumorigenesis. MTH1 is the main mammalian 8-oxodGTPase that is known to be elevated in various RAS-driven cancers including PDAC. We have previously shown MTH1 is critical for ROS-mediated oncogenic signaling, and promotes escape from oncogene-induced senescence. We therefore hypothesized that MTH1 provides important redox support for aggressive PDAC tumor growth. Consistent with this, we found that elevated MTH1 expression was strongly correlated with poor disease-free survival in PDAC patients. These findings extended to KRAS-driven PDAC cell lines: highly proliferative human PDAC cells strongly expressed MTH1 (MTH1high), and MTH1 deletion was selectively anti-tumorigenic against MTH1high cells. Furthermore, introduction of MTH1-null backgrounds into gold standard genetically engineered PDAC mouse models selectively decreased 8-oxodGTPase activity levels and slowed PDAC growth in aggressive, short latency Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice, but with no effect in longer latency Pdx1Cre; LSL- KrasG12D/+; LSL-Trp53R172H/+ (KPC) mice. These selective anti-tumorigenic effects were accompanied by a reduction in circulating immunosuppressive cytokines in PKT mice, further suggesting that MTH1 potentially supports aggressive tumorigenesis through induction of systemic immunosuppression. Consistent with this, pancreatic-restricted MTH1 conditional deletion fully rescued PDAC growth in PKT mice. Our findings here thus suggest that MTH1-dependent redox protection of the nucleotide pool represents a unique TME adaptation that supports aggressive PDAC tumorigenesis. Further studies will investigate whether this adaptation is maintained through symbiotic tumor/stroma or tumor/immune cell crosstalk, as observed for other KRAS-driven traits. Ultimately, interventions designed to target MTH1-dependent protection of the nucleotide pool could hold promise as novel therapeutic strategies for this untreatable disease. Citation Format: Beatriz Mateo-Victoriano, Ling Zhang, Jaya Samaranayake, Z McGaughey, Cassie Due, Clara Troccoli, Michael G. Mohsen, Nagaraj Nagathihalli, Oliver G. McDonald, Michael VanSaun, Eric T. Kool, Priyamvada Rai. The mammalian 8-oxo-dGTPase, MTH1, as a novel targetable vulnerability in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2967.