What question did this study set out to answer?

The study aims to identify molecular determinants of radiation sensitivity, focusing on MDM2's role in lung adenocarcinoma with TP53 wild-type.

April 5, 2026

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

Key Points

The study aims to identify molecular determinants of radiation sensitivity, focusing on MDM2's role in lung adenocarcinoma with TP53 wild-type.
Lung adenocarcinoma cell lines were assessed for sensitivity to ionizing radiation (IR) using clonogenic assays.
Transcriptomic profiles and CRISPR dependency datasets were integrated to find molecular targets.
Pharmacological inhibition of MDM2 (idasanutlin) was tested alone and combined with IR across various LUAD lines.
Treatment responses were evaluated using clonogenic assays, 3D spheroid cultures, and xenografts.
Distinct IR-sensitive and IR-insensitive LUAD cell line subsets were identified based on clonogenic survival.
MDM2 dependency was significantly higher in TP53 wild-type, IR-insensitive cells, indicating a link to radioresistance.
Idasanutlin monotherapy showed greater growth inhibition in TP53 wild-type cells than in p53-mutant cells.
The combination of idasanutlin and IR resulted in significant cytotoxicity and reduced cell survival in various assays.
In vivo, idasanutlin combined with IR achieved 77.1% tumor growth inhibition with no body weight loss.

Abstract

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.

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