Preclinical comparison of radiobiological and radiosensitizing effects in peptide receptor radionuclide therapy and external beam radiotherapy

Peptide receptor radionuclide therapy (PRRT) is an established treatment for advanced neuroendocrine tumors (NETs), yet complete responses are uncommon. Combining PRRT with radiosensitizing agents may enhance therapeutic efficacy, but rational design of such combinations requires insight into PRRT-specific radiobiology, which is often extrapolated from external beam radiotherapy (EBRT). We performed a head-to-head comparison of NET cell responses to PRRT and EBRT using transcriptomic profiling at two time points. Based on outcomes of the pathway analysis, we screened a focused library of compounds targeting DNA damage response (DDR) and cell cycle regulators to identify potential radiosensitizers. Selected hits were validated in GOT1 and NCI-H69 cells through viability assays and dose-response modeling. Radiosensitization was quantified using α-enhancement factors and relative biological effectiveness (RBE). Both radiation modalities activated overlapping stress-response programs dominated by DDR and cell cycle pathways, although PRRT exhibited a delayed transcriptional peak compared to EBRT. High-throughput screening revealed multiple radiosensitizing candidates, including inhibitors of DNA-PKcs, ATR, ATM, PARP, and HSP90, with marked cell line-specific differences. Validation experiments confirmed strong sensitization by DNA-PKcs inhibition across both modalities, while other targets showed context-dependent effects. Dose-response analysis indicated comparable radiosensitizing potential for EBRT and PRRT, despite differences in intrinsic RBE. Our findings demonstrate that DDR-targeted compounds can enhance PRRT efficacy to a similar extent as EBRT, supporting the translational relevance of EBRT-derived radiosensitizer strategies for PRRT. However, pronounced variability between cell models underscores the need for biomarker-driven approaches. These results provide a framework for rational combination design and highlight DNA-PKcs inhibition as a promising candidate for clinical evaluation.