Abstract 5276: 123ICC1, a radiopharmaceutical for Targeted radionuclide therapy (TRT), exploits PARP binding and trapping to amplify DNA damage and cytotoxicity in human cancer cell lines

Abstract We investigated whether the antitumor effects of 123ICC1, a PARP-binding radiopharmaceutical emitting very short-range ionising Auger electrons with potential use in Targeted Radionuclide Therapy (TRT), are driven by PARP trapping. Trapping will prolong its residence time on DNA and triggers more DNA damage. We tested this in PSN1 and U87 human cancer cell lines exposed to 123ICC1, by assessing PARP levels in the chromatin fraction via western blot and quantifying 123I counts in nuclear and cytoplasmic fractions using a gamma counter. Downstream effects were evaluated using γH2AX immunofluorescence as a marker of DNA damage and DNA fiber assays to measure replication speed. Furthermore, we modulated PARP association with DNA by using methyl methanesulfonate (MMS) to increase and the PARG inhibitor JA2131 to decrease trapped PARP, using western blot and gamma counter to analyze how 123ICC1 tracks PARP movements from chromatin to nuclear soluble fraction. Finally, γH2AX immunofluorescence was used to assess whether combinatory treatments with MMS or PARGi affect the ability of 123ICC1 in producing DNA damage. 123ICC1 elevated trapped PARP levels on DNA in PSN1 and U87 cells, followed by a rapid increase in γH2AX foci. Interestingly, DNA fiber assays showed that replication was markedly hindered in PSN1 at 30 min and 24 h, indicating substantial DNA damage. Pretreatment with 0.01% MMS before 123ICC1 addition further elevated PARP levels compared to 123ICC1 alone, resulting in greater chromatin 123I accumulation. In contrast, PARG inhibitor treatment reduced PARP residence time on DNA, and in combination with 123ICC1 decreased DNA 123I delivery. Finally, assessment of γH2AX at 30 min and 24 hours showed that MMS pretreatment enhanced DNA damage induced by 123ICC1 greater damage than MMS alone, demonstrating an additive effect, whereas PARGI pretreatment had no significant effect.The results indicate that the cytotoxic effect of 123ICC1 is mediated by PARP trapping, which underlies its potent antitumoral activity previously observed by our group. Furthermore, modulation of the PARylation cycle alters delivery of radioactivity to DNA and the extent of DNA damage, suggesting a strategy to enhance the therapeutic benefit of 123ICC1 and its potential for clinical translation. Citation Format: Luis Hernandez Cano, Nerea Delgado Mayenco, Hilleen Kramer, Elmar Diekstra, Francesca Amoroso, George Alachouzos, Wiktor Szymanski, Frank A. Kruyt, Bart Cornelissen. 123ICC1, a radiopharmaceutical for Targeted radionuclide therapy (TRT), exploits PARP binding and trapping to amplify DNA damage and cytotoxicity in human cancer cell lines abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5276.