Abstract 2916: DNA polymerase theta inhibitor, ART6043, potentiates the efficacy of 177Lu- and 225Ac-based radioligand therapies in vitro and in vivo

Abstract DNA polymerase theta (Polθ) is a DNA repair enzyme critical for microhomology mediated end joining (MMEJ). Loss or inhibition of Polθ has been shown to potentiate external beam radiation in a tumour-specific manner1,2. However, the ability of Polθ inhibitors to potentiate open source radiation has not been explored. This potential is pertinent to cancer therapy, as radioligand therapy (RLT), where a radionuclide is targeted to tumour cells by linking to peptides binding tumour-specific receptors, has had recent clinical success, in particular with 177Lu-PSMA-617 for prostate cancer. Hence, we investigated the ability of the clinical Polθ inhibitor, ART60433, to potentiate different forms of RLT. Here, we show that ART6043 treatment significantly potentiate the cell killing activity of 177Lu-RLT and 225Ac-RLT in different prostate cancer cell models. Mechanistic studies show that the combination of ART6043 with 177Lu-RLT caused a significant activation of DNA damage response pathways, accumulation of DNA damage and an increase in apoptosis compared to RLT or ART6043 alone. Key findings were confirmed for the combination of ART6043 with 225Ac-RLT.Furthermore, in vivo studies in mouse prostate cancer xenografts showed that the combination of ART6043 with 177Lu-RLT induced significant tumour growth inhibition and a significant improvement in median survival with regimens that were well tolerated. This work supports the clinical development of the combination of ART6043 with RLT to improve the clinical efficacy of RLT. References: 1 Rodriguez-Berriguete G, Ranzani M, et al., Clin Cancer Res. 2023. 2 Higgins GS, et al., Cancer Res. 2010. 3 NCT05898399. Citation Format: Marco Ranzani, Alessandro Cicconi, Joseph Barlow, Paula Costales, Elias Elias, Alessandro Galbiati, Jayesh B. Majithiya, Silvia Peripolli, Eeson Rajendra, Marina Roy-Luzarraga, Nan Shao, Martin L. Stockley, Asmita Thapa, Robert A. Heald, Graeme C. Smith, Helen M. Robinson. DNA polymerase theta inhibitor, ART6043, potentiates the efficacy of 177Lu- and 225Ac-based radioligand therapies in vitro and in vivo [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 2916.