Abstract 2905: Combination of the ATR inhibitor, ART0380, with irinotecan for treating ATM-negative tumors

Abstract Ataxia telangiectasia mutated (ATM) and Ataxia telangiectasia and Rad3-related (ATR) proteins function in concert to regulate the cellular response to both intrinsic and extrinsic factors that induce replication stress such as oncogene activation and DNA damaging agents. Loss or inhibition of ATR has been well documented to be synthetic lethal with ATM deficiency in cancers and this concept is being explored in clinical trials, however, the efficacy of monotherapy with ATR inhibitors has been limited with objective response rates of ∼10%. Here, using a novel ATR kinase inhibitor, ART0380, we provide mechanistic preclinical evidence that exacerbating replication stress with a low dose of the TOPO1 inhibitor, irinotecan, further sensitizes ATM negative tumors to ATR inhibition. This enhanced cancer cell killing by the combination of ART0380 and irinotecan in ATM negative cells is linked to loss of cell cycle control and entry of ATM negative cancer cells into mitosis with DNA damage, leading to mitotic catastrophe. In a range of CDX and PDX mouse models we show that the combination of ART0380 with irinotecan leads to robust tumor growth inhibition and, in some instances, regressions across diverse ATM negative tumor types and is well tolerated. These findings highlight ART0380 in combination with low-dose irinotecan as a promising therapeutic strategy for ATM negative cancers, which supports the ongoing clinical investigation NCT04657068. Citation Format: Helen M. Robinson, Desiree Piscitello, Elias Elinati, Lucy Armstrong, Emily Graham, Silvia Peripolli, Giorgia Lillo, Joana F. B. P. Neves, Jayesh Majithiya, Eeson Rajendra, Marina Roy-Luzarraga, Lerin Geo, Vera Grinkevich, Ian C. Smith, Alessandro Galbiati, Arya Ashok Nair, Graeme C. Smith. Combination of the ATR inhibitor, ART0380, with irinotecan for treating ATM-negative tumors [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 2905.