Abstract 4636: Deciphering radiation sensitivity identifies MDM2 as a targetable driver of synergistic radiosensitization in TP53 wild-type lung adenocarcinoma

Abstract Background: Resistance to ionizing radiation (IR) remains a major obstacle to effective radiotherapy. Beyond its classical role as a negative regulator of p53, MDM2’s broader contribution to radioresistance remains insufficiently understood. Given that lung adenocarcinoma (LUAD) exhibits heterogeneous responses to radiotherapy, defining molecular determinants of radiation sensitivity may reveal actionable targets. In this context, we sought to identify such determinants and to determine whether MDM2 represents a critical and therapeutically targetable regulator capable of enhancing radiotherapy efficacy in LUAD. Methods: LUAD cell lines (A549, NCI-H460, NCI-H650, NCI-H1573) were stratified into IR-sensitive and IR-insensitive groups using clonogenic survival following irradiation. Transcriptomic profiles and DepMap CRISPR dependency datasets were integrated to uncover potential molecular determinants of radiation sensitivity. Pharmacologic MDM2 inhibition (idasanutlin) was tested alone or in combination with IR across LUAD cell lines with distinct TP53 backgrounds. Clonogenic assays, 3D spheroid cultures, and xenografts were used to assess treatment responses in 2D, 3D, and in vivo settings. Results: Clonogenic survival analysis revealed distinct IR-sensitive and IR-insensitive subsets among LUAD cell lines. Integrated analyses demonstrated that MDM2 dependency was markedly higher in TP53 wild-type IR-insensitive cells, suggesting a p53-proficient context for MDM2-driven radioresistance. In line with this prediction, MDM2 inhibition alone (idasanutlin monotherapy) induced more pronounced growth inhibition in p53 wild-type compared with p53-mutant cells. The IR-idasanutlin combination produced robust synergistic cytotoxicity, profoundly reducing clonogenic survival and causing spheroid shrinkage accompanied by markedly elevated EthD-1 fluorescence intensity, indicating increased cell death. In an NCI-H460 xenograft model, idasanutlin (15 mpk, p.o. daily) combined with IR (4 Gy) yielded the highest tumor growth inhibition (TGI = 77.1%, p 0.001) without body-weight loss, demonstrating strong in vivo synergistic efficacy and tolerability. These findings underscore the translational potential of MDM2 blockade as a radiosensitizing strategy in p53-proficient tumors. Conclusions: Our findings demonstrate that MDM2 dependency, revealed through integrative omics analyses, represents a therapeutic vulnerability underlying IR-resistance in p53-proficient LUAD. Combining idasanutlin with radiotherapy effectively overcomes this resistance, highlighting MDM2 as a robust and actionable target for enhancing radiation response in cancers driven by high MDM2 activity. Citation Format: Chan Hoon Maeng, Jieon Hwang, Joong Bae Ahn, Sang Joon Shin. Deciphering radiation sensitivity identifies MDM2 as a targetable driver of synergistic radiosensitization in TP53 wild-type lung adenocarcinoma 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 4636.