Abstract 2896: Transforming treatment paradigms: A cutting-edge polθ Inhibitor (DWP223) targeting PARP resistance in BRCA-mutant cancers

Abstract A significant portion of tumors with BRCA1 or BRCA2 mutations exhibit only weak responses to PARP inhibitor (PARPi) treatment, and often develop resistance to PARPi over time. Both Polθ and PARP1 play critical roles in MMEJ for DNA double-strand break repair, and Polθ inhibition holds the potential to overcome PARPi resistance driven by BRCA reversion mutations. To address these challenges, we have developed DWP223, a novel selective and potent Polθ inhibitor. This compound can be used as a single agent or in combination with PARPi to treat tumors harboring BRCA mutations.DWP223 has shown potent and selective inhibition of BRCA-deficient cell proliferation in vitro, achieving an IC50 value below 20 nM, while demonstrating minimal impact on parental cell lines. In vivo, DWP223 monotherapy is effective at doses as low as 30 mg/kg, and when used in combination with PARP inhibitors, it induces over 50% tumor regression at a lower dose. Notably, even at high doses, DWP223 is well-tolerated, with no observable weight loss or hematological toxicity in animal models.Furthermore, DWP223 extends therapeutic potential by exhibiting synthetic lethality in tumors deficient in non-homologous recombination (HR), broadening its application to patients without homologous recombination repair (HRR) mutations. The compound’s favorable pharmacokinetic profile and robust safety data across multiple species underscore its suitability for clinical development, highlighting the opportunity to reduce hematological toxicity and target PARP inhibitor-resistant cancers.Collectively, DWP223 represents a promising therapeutic candidate, either as a standalone treatment or in combination with PARPi, for targeting HR-deficient cancers and potentially overcoming PARPi resistance. DWP223 is advancing toward IND filing in 2025. Citation Format: Juno Kim, Jie Luo, Bin Cao, Ling Zhao, Xiaojing Zhang, Xiaohua Lin, Xiaojing Lin. Transforming treatment paradigms: A cutting-edge polθ Inhibitor (DWP223) targeting PARP resistance in BRCA-mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2896.