Abstract 436: Redox-DNA repair co-targeting with IP-DNQ and rucaparib induces oxidative DNA damage and GSDME-mediated pyroptosis in NQO1-positive tumors.

Abstract Cancer remains a leading cause of mortality worldwide, with current therapies often failing to eradicate resistant tumor populations. This highlights the need for strategies that exploit tumor-specific metabolic and DNA repair vulnerabilities. NAD(P)H:quinone oxidoreductase 1 (NQO1), commonly overexpressed in solid tumors, enzymatically activates redox-cycling prodrugs, offering a selective tumor targeting strategy. Isopentyl-deoxynyboquinone (IP-DNQ), a potent NQO1-bioactivatable quinone, undergoes futile redox cycling to generate reactive oxygen species (ROS), induce oxidative DNA damage, and deplete NAD+/ATP. Given that PARP activation is an early response to DNA damage, we investigated the mechanistic synergy between NQO1-dependent redox cycling and PARP inhibition using IP-DNQ combined with rucaparib, an FDA-approved PARP inhibitor. Rucaparib significantly enhanced IP-DNQ-induced ROS accumulation, DNA strand breaks, and metabolic collapse in an NQO1-dependent manner. This combination triggered caspase-3 activation and gasdermin E (GSDME) cleavage, leading to pyroptotic cell death characterized by LDH release and IL-1β secretion. Both pharmacologic inhibition and genetic knockout of NQO1 abolished these effects, confirming the essential role of IP-DNQ bioactivation. Importantly, the IP-DNQ/rucaparib combination suppressed tumor growth and prolonged survival in orthotopic pancreatic and lung cancer models without causing systemic toxicity. These findings uncover a novel redox-DNA repair co-targeting strategy that amplifies oxidative DNA damage and redirects apoptosis toward immunogenic GSDME-mediated pyroptosis. This approach broadens the therapeutic scope of PARP inhibitors and offers a promising platform for treating NQO1-overexpressing cancers. Citation Format: Soumya Tumbath, Hao Zhou, Jiangwei Wang, Lingxiang Jiang, Elin H. Chen, Celine Thormann, Xiumei Huang. Redox-DNA repair co-targeting with IP-DNQ and rucaparib induces oxidative DNA damage and GSDME-mediated pyroptosis in NQO1-positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 436.