Abstract 312: The ATR inhibitor ART0380 shows preclinical efficacy in monotherapy or in combination with gemcitabine, aPD1, PARP inhibitors and topoisomerase 1 poisons

Abstract

Abstract ART0380 is a potent, selective and orally active inhibitor of ataxia telangiectasia and Rad3-related (ATR) that has been developed for treatment for cancer patients with DNA repair defects. Here we show preclinical data of ART0380 in a range of tumour xenograft models, both as monotherapy and in combination with other DNA-damaging agents. As monotherapy, ART0380 exhibits tumour PD (γH2AX) effects and efficacy comparable to the ATR inhibitor BAY-1895344 but causing less toxicity to the gut. As ATM has been highlighted as synthetic lethal with ATR, ART0380 monotherapy was also evaluated in ATM-deficient models showing strong tumour growth inhibition using both continuous and intermittent scheduling. ART0380 was also shown to have enhanced efficacy when dosed in combination with other anti-cancer agents. Here we show strong synergy when combining ART0380 with gemcitabine, the PARP inhibitor olaparib, the topoisomerase 1 poison irinotecan as well as the immuno-oncology therapeutic aPD1. Overall, these data demonstrate the high potential of ART0380 as an anti-cancer agent given as monotherapy or in combination Citation Format: Jayesh Bhanabhai Majithiya, Marina Roy Luzarraga, Richard Newman, Paula Costales, Philip Jones, Maria Emilia Di Francesco, Virginia Giuliani, Chris Caroll, Mary Geck Do, Tim Heffernan, Ningpeng Feng, XiaoYan Ma, Sarah lively, Michael G. Johnson, Lerin Geo, Desiree Piscitello, Eeson Rajendra, Vera Grinkevich, Marco Ranzani, Martin Stockley, Gillian Langford, Robert Heald, Helen M. Robinson, Graeme C. Smith. The ATR inhibitor ART0380 shows preclinical efficacy in monotherapy or in combination with gemcitabine, aPD1, PARP inhibitors and topoisomerase 1 poisons [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 312.