Radiogenomics and the DNA damage response: opportunities for biomarker-guided radiosensitization in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis, despite significant research efforts. The use of radiotherapy (RT) in PDAC treatment is constrained by intrinsic PDAC radioresistance and concern for normal tissue toxicity. Radiogenomics, the study of how genetic variants may influence RT response, could be incorporated into PDAC treatment. This approach offers a framework for personalized RT dosing guided by individual genomic data. Additionally, DNA damage response (DDR) inhibitors may sensitize PDAC to ionizing radiation to increase the targeted effectiveness of RT. This review examines the history and progress of radiogenomics, spanning from genome-wide approaches to more recent algorithm-based indices such as the radiosensitivity index (RSI) and the genomic-adjusted radiation dose (GARD). These approaches are promising but require additional validation in PDAC due to inconsistent findings across studies and inadequate PDAC-specific data. We also evaluate clinical advances in the development of inhibitors targeting key DDR elements such as ATR, ATM, CHK1/2, WEE1, DNA-PKcs, and PARP. Finally, we highlight emerging strategies for targeting KRAS G12D in PDAC. Collectively, these approaches offer an avenue for reducing radioresistance in PDAC while improving treatment response and minimizing normal tissue toxicity. Future research directions should include the incorporation of multi-omics data into predictive models for appropriate treatment selection, additional large-scale, biomarker-driven clinical trials, and continued integration of biomarker-targeting drug therapy, radiotherapy, and immunotherapy into treatment regimens.