ReviewBiological determinants of radioresistance and their remediation in pancreatic cancer

•A majority of pancreatic cancer (PC) patients do not respond to radiotherapy.•Mutations and altered signaling pathways in PC cells have roles in radiation resistance by affecting DNA damage sensing, DNA repair, cell cycle checkpoints, and cell survival.•Potential radiosensitizers tested in clinical trials for PC include chemotherapy (5-FU, gemcitabine, capecitabine), oxygen substitutes (nitroimidazoles), EGFR inhibitors (cetuximab, erlotinib), nelfinavir, HDAC inhibitors, and prenyltransferase inhibitors.•A number of synthetic drugs and natural products have been tested as radiosensitizers or radioprotectants for PC in preclinical studies.

Despite recent advances in radiotherapy, a majority of patients diagnosed with pancreatic cancer (PC) do not achieve objective responses due to the existence of intrinsic and acquired radioresistance. Identification of molecular mechanisms that compromise the efficacy of radiation therapy and targeting these pathways is paramount for improving radiation response in PC patients. In this review, we have summarized molecular mechanisms associated with the radio-resistant phenotype of PC. Briefly, we discuss the reversible and irreversible biological consequences of radiotherapy, such as DNA damage and DNA repair, mechanisms of cancer cell survival and radiation-induced apoptosis following radiotherapy. We further describe various small molecule inhibitors and molecular targeting agents currently being tested in preclinical and clinical studies as potential radiosensitizers for PC. Notably, we draw attention towards the confounding effects of cancer stem cells, immune system, and the tumor microenvironment in the context of PC radioresistance and radiosensitization. Finally, we discuss the need for examining selective radioprotectors in light of the emerging evidence on radiation toxicity to non-target tissue associated with PC radiotherapy.