title: Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation.
abstract: Combined radiochemotherapy is the currently used therapy for locally advanced pancreatic ductal adenocarcinoma (PDAC), but normal tissue toxicity limits its application. Here we test the hypothesis that inhibition of ATR (ATM-Rad3-related) could increase the sensitivity of the cancer cells to radiation or chemotherapy without affecting normal cells. We tested VE-822, an ATR inhibitor, for in vitro and in vivo radiosensitization. Chk1 phosphorylation was used to indicate ATR activity, γH2AX and 53BP1 foci as evidence of DNA damage and Rad51 foci for homologous recombination activity. Sensitivity to radiation (XRT) and gemcitabine was measured with clonogenic assays in vitro and tumor growth delay in vivo. Murine intestinal damage was evaluated after abdominal XRT. VE-822 inhibited ATR in vitro and in vivo. VE-822 decreased maintenance of cell-cycle checkpoints, increased persistent DNA damage and decreased homologous recombination in irradiated cancer cells. VE-822 decreased survival of pancreatic cancer cells but not normal cells in response to XRT or gemcitabine. VE-822 markedly prolonged growth delay of pancreatic cancer xenografts after XRT and gemcitabine-based chemoradiation without augmenting normal cell or tissue toxicity. These findings support ATR inhibition as a promising new approach to improve the therapeutic ration of radiochemotherapy for patients with PDAC.
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Oxford University, Oxford, UK.
authors.forename: E
authors.initials: E
authors.lastname: Fokas
authors.forename: R
authors.initials: R
authors.lastname: Prevo
authors.forename: J R
authors.initials: JR
authors.lastname: Pollard
authors.forename: P M
authors.initials: PM
authors.lastname: Reaper
authors.forename: P A
authors.initials: PA
authors.lastname: Charlton
authors.forename: B
authors.initials: B
authors.lastname: Cornelissen
authors.forename: K A
authors.initials: KA
authors.lastname: Vallis
authors.forename: E M
authors.initials: EM
authors.lastname: Hammond
authors.forename: M M
authors.initials: MM
authors.lastname: Olcina
authors.forename: W
authors.initials: W
authors.lastname: Gillies McKenna
authors.forename: R J
authors.initials: RJ
authors.lastname: Muschel
authors.forename: T B
authors.initials: TB
authors.lastname: Brunner
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage*; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*
chemical_list: D018797:Cell Cycle Proteins; D007555:Isoxazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011838:Radiation-Sensitizing Agents; D011494:Protein Kinases; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D017346:Protein Serine-Threonine Kinases; C000598331:berzosertib