Abstract
Abstract Tumors that are deficient in homologous recombination repair are generally sensitive to agents that target pathways involved in DNA repair, including PARP inhibitors (PARPi) and platinum-based drugs. Despite the clinical benefit of PARP1/2 inhibitors, which are FDA-approved for the treatment of certain BRCA-mutant cancers, many patients achieve incomplete disease control and develop resistance. PARP inhibitors have been shown to synergize with chemotherapy and platinum-based drugs, but such combinations are limited clinically due to overlapping toxicities, highlighting the need for novel combination strategies. We previously reported on the identification of USP1 as a target that selectively kills BRCA1/2-mutant cancer cells. TNG348 is an oral, allosteric and potent inhibitor of USP1 (USP1i). Here we present the mechanism of action and preclinical efficacy of TNG348 across multiple BRCA1/2 mutant and other homologous recombination deficient (HRD) tumor models, demonstrating its therapeutic potential. In preclinical models, TNG348 activity is further enhanced when combined with agents targeting DNA repair pathways, including PARP inhibitors. In a PDX model of acquired PARPi resistance, TNG348 demonstrates strong combination activity with PARPi demonstrating the ability of USP1i + PARPi to restore sensitivity to PARPi in the setting of acquired resistance. CRISPR-based drug anchor screens with and without PARPi or USP1i reveal that this synergy is driven by non-overlapping mechanisms of action. While sensitivity to either USP1i or PARPi is associated with HRD status, resistance to PARPi, but not USP1i, occurred with knock out of shieldin components, 53BP1, PARG and other previously reported mechanisms. In contrast, resistance to USP1i was uniquely gained by knocking out genes involved in PCNA ubiquitination and translesion synthesis. In summary, these data support the clinical development plan to evaluate TNG348 in patients with BRCA1/2 mutant and other HRD tumors as single agent and in combination with PARPi. Citation Format: Antoine Simoneau, Charlotte Pratt, Grace Comer, Hsin-Jung Wu, Ashley Choi, Tenzing Khendu, Samuel Meier, Yi Yu, Shangtao Liu, Wenhai Zhang, Douglas Whittington, William Mallender, Sirimas Sudsakorn, Yingnan Chen, Brian Haines, Scott Throner, Adam Crystal, Alan Huang, John Maxwell, Jannik Andersen. TNG348, a selective USP1 inhibitor, shows strong preclinical combination activity with PARP inhibitors and other agents targeting DNA repair [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B054.
Published Version
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