KEY POINTS
- The study evaluated two pancreatic ductal adenocarcinoma cell lines: KRAS wild-type BxPC-3 and KRAS G12D-mutated PANC-1, testing whether inhibition of DNA-damage-response and cell-cycle pathways could enhance radiation-induced immunogenicity.
- Cells received single-dose 8 Gy X-rays, 8 Gy carbon ions, or hypofractionated X-rays of 3 × 8 Gy, combined with ATR, CHK1, ATM, PARP or WEE1 inhibition or the STING agonist diABZI.
- ATR inhibition strongly sensitized both cell lines to radiation-induced clonogenic death. Carbon ions produced greater dose-dependent cytotoxicity than X-rays at the same physical dose.
- In BxPC-3 cells, ATR inhibition combined with 3 × 8 Gy increased ATP release, cytosolic double-stranded DNA, micronuclei and mitotic catastrophe, supporting enhanced immunogenic cell death.
- ATR inhibition amplified STING-dependent IFNB1 expression and inflammatory transcriptional programmes in BxPC-3 cells. These effects were less pronounced after single-dose irradiation than after hypofractionated X-rays.
- Supernatants from treated BxPC-3 cells increased monocyte activation, whereas irradiated PANC-1 supernatants produced weaker or immunosuppressive effects, indicating substantial biological heterogeneity.
- The differential response was observed between only two cell lines and cannot establish KRAS status as a clinical predictive biomarker.
CLINICAL TAKEAWAY
ATR inhibition may enhance both tumour-cell killing and innate immune activation after photon or carbon ion radiotherapy in selected pancreatic cancers. The apparent KRAS-dependent difference is hypothesis-generating and requires validation in animal models and biomarker-driven clinical studies.