Abstract LB271: Synergistic anti-tumor efficacy in olaparib-sensitive and -resistant models via simultaneously inhibition of USP1 and PARP

Abstract

Abstract SIM0501 is a potent, orally bioavailable, specific inhibitor for USP1. We have explored its combination with olaparib, an approved PARP inhibitor, in both in vitro cancer cell lines and in vivo tumor models. Specifically, SIM0501 showed synergistic effect with olaparib on cell lines across different cancer types, including breast, ovarian, and prostate cancers. Most of these cell lines contain mutations in the homologous recombinational repair (HRR) pathway, which is likely the reason for their susceptibility to the combined inhibition on USP1 and PARP. In the in vivo efficacy studies, SIM0501 dose-dependently inhibited tumor growth when combined with olaparib, including BRCA1-mutated MDA-MB-436, BRCA-wildtype olaparib-resistant OVCAR3, and olaparib-resistant ovarian PDX models. Further, in the MDA-MB-436 model, delayed addition of olaparib to SIM0501 showed comparable efficacy with simultaneous combination treatment, suggesting the flexibility in add-on dosing strategy. Regarding the biomarker research, dose-dependent increase of Ub-PCNA was demonstrated by western blot (WB) following in vivo efficacy studies. Moreover, we have developed robust IHC detection method for Ub-PCNA, which correlated well with WB results. Since Ub-PCNA is a direct target of USP1, these results will facilitate the clinical assessment of target engagement by SIM0501. In summary, SIM0501 demonstrates strong synergistic anti-tumor growth effect in combination with PARP inhibitors in both in vitro and in vivo pharmacology studies, which supports the clinical testing of SIM0501, in combination with PARP inhibitors in patients harboring HRR mutations. Citation Format: Shuqun Yang, Zhengtao Li, Lei Zhou, Feng Zhou, Xiaokang Qin, Liting Xue, Piaopiao Xu, Jianxing Tang, Wendy Wang, Renhong Tang. Synergistic anti-tumor efficacy in olaparib-sensitive and -resistant models via simultaneously inhibition of USP1 and PARP [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB271.