Toward biomarker-guided radiotherapy: Multi-omics analysis links ATM status to radioresistance in lung adenocarcinoma

Lung adenocarcinoma (LUAD) exhibits wide variability in radiotherapy response, yet no validated biomarkers currently guide radiation stratification. The ataxia-telangiectasia mutated (ATM) kinase plays a central role in DNA damage repair, and its loss has been associated with radiosensitivity. This study aimed to identify molecular determinants of radiosensitivity in LUAD and to evaluate the impact of ATM status and pharmacological ATM inhibition on radiation response. Radiosensitivity of five LUAD cell lines was assessed using clonogenic, MTS, and impedance-based assays. The selective ATM inhibitor AZD1390 was used to test radiosensitization in ATM-proficient versus ATM-deficient models. Transcriptomic and proteomic profiles after irradiation (2 Gy) were analyzed by RNA sequencing and data-independent acquisition mass spectrometry across multiple time points. ATM protein deficiency correlated positively with enhanced radiosenesitivity (p < 0.01). Pharmacological inhibition of ATM with AZD1390 markedly increased radiosensitivity in ATM-proficient but not in ATM-deficient cells. Comparative multi-omics analyses revealed differential regulation of candidate effectors, including RAB39A/B and KDF1, whose expression patterns were associated with ATM status and radiation response. Time-resolved proteomics indicated that ATM-proficient cells upregulated cell-cycle and spindle-assembly proteins within 6 h post-irradiation, whereas ATM-deficient cells exhibited downregulation of mitochondrial ribosomal proteins at later time points. ATM status is a major determinant of intrinsic radiosensitivity in LUAD cell models. Our data suggest that ATM inhibition may serve as a promising radiosensitization strategy for ATM-proficient tumors, while RAB39A/B and KDF1 emerge as exploratory candidates for further validation as ATM-associated biomarkers. These findings support the development of biomarker-guided approaches to personalize radiotherapy in lung adenocarcinoma.