What question did this study set out to answer?

This research aims to develop a strategy that targets NQO1-overexpressing tumors by combining IP-DNQ and rucaparib to enhance DNA damage and induce cell death.

April 4, 2026

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

Key Points

This research aims to develop a strategy that targets NQO1-overexpressing tumors by combining IP-DNQ and rucaparib to enhance DNA damage and induce cell death.
Investigated the effects of IP-DNQ and rucaparib on oxidative DNA damage.
Measured the accumulation of reactive oxygen species and DNA strand breaks.
Assessed cell death mechanisms, including pyroptosis and caspase activity.
Utilized pharmacologic inhibition and genetic knockout of NQO1 to validate findings.
Conducted experiments in orthotopic pancreatic and lung cancer models.
IP-DNQ combined with rucaparib led to increased ROS and DNA damage.
The combination triggered GSDME-mediated pyroptosis, characterized by LDH release and IL-1β secretion.
NQO1 inhibition abolished the effects, confirming the role of IP-DNQ bioactivation.
The treatment significantly suppressed tumor growth and extended survival in cancer models.
No systemic toxicity was observed in the treated models.

Abstract

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.

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