Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor survival rate, and most patients are not eligible for surgery. Radiation therapy has limited benefit because PDAC tumors are naturally resistant to radiation, using strategies such as low oxygen levels, strong DNA repair systems, and altered cell cycles to survive. To improve radiation effectiveness, researchers are developing radiosensitizers that make cancer cells more vulnerable to radiation damage.
One long-used approach is combining radiation with chemotherapy drugs like gemcitabine or 5-fluorouracil. These drugs interfere with DNA production and repair, increasing radiation-induced damage. However, clinical benefits have been inconsistent, so their use is limited. Newer strategies focus on blocking the tumor’s DNA damage repair pathways. Drugs targeting key repair proteins such as ATR, ATM, DNA-PK, Wee1, and PARP aim to prevent cancer cells from fixing radiation-induced DNA breaks. Among these, Wee1 inhibitors have shown particularly promising survival benefits in early trials, while others remain under active investigation.
Another emerging approach uses nanoparticles to physically enhance radiation effects within tumors. Gold and gadolinium-based nanoparticles can amplify radiation damage by increasing local energy release and reactive oxygen species, while also aiding imaging. Overall, while traditional chemotherapy remains the main radiosensitizer, future progress in PDAC is likely to come from precision targeting of DNA repair pathways and nanotechnology, pending confirmation in larger clinical trials.