title: Biological determinants of radioresistance and their remediation in pancreatic cancer.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Omaha, NE, United States.
authors.forename: Parthasarathy
authors.initials: P
authors.lastname: Seshacharyulu
authors.affiliation: Fred & Pamela Buffett Cancer Center, Omaha, NE, United States; Department of Radiation Oncology, Omaha, NE, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Baine
authors.affiliation: Department of Biochemistry and Molecular Biology, Omaha, NE, United States.
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Souchek
authors.affiliation: Department of Biochemistry and Molecular Biology, Omaha, NE, United States.
authors.forename: Melanie
authors.initials: M
authors.lastname: Menning
authors.affiliation: Department of Biochemistry and Molecular Biology, Omaha, NE, United States.
authors.forename: Sukhwinder
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Department of Radiation Oncology, Omaha, NE, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, NE, United States.
authors.forename: Michel M
authors.initials: MM
authors.lastname: Ouellette
authors.affiliation: Department of Biochemistry and Molecular Biology, Omaha, NE, United States.
authors.forename: Maneesh
authors.initials: M
authors.lastname: Jain
authors.affiliation: Fred & Pamela Buffett Cancer Center, Omaha, NE, United States; Department of Radiation Oncology, Omaha, NE, United States.
authors.forename: Chi
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology, Omaha, NE, United States; Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE, United States; Fred & Pamela Buffett Cancer Center, Omaha, NE, United States. Electronic address: sbatra@unmc.edu.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D006801:Humans; D010190:Pancreatic Neoplasms / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000502:physiology*; D059016:Tumor Microenvironment / Q000528:radiation effects