title: Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation.
abstract: We show that ATM kinase inhibition using AZ31 prior to 9 or 9.25 Gy total body irradiation (TBI) reduced median time to moribund in mice to 8 days. ATR kinase inhibition using AZD6738 prior to TBI did not reduce median time to moribund. The striking finding associated with ATM inhibition prior to TBI was increased crypt loss within the intestine epithelium. ATM inhibition reduced upregulation of p21, an inhibitor of cyclin-dependent kinases, and blocked G1 arrest after TBI thereby increasing the number of S phase cells in crypts in wild-type but not Cdkn1a(p21CIP/WAF1)-/- mice. In contrast, ATR inhibition increased upregulation of p21 after TBI. Thus, ATM activity is essential for p21-dependent arrest while ATR inhibition may potentiate arrest in crypt cells after TBI. Nevertheless, ATM inhibition reduced median time to moribund in Cdkn1a(p21CIP/WAF1)-/- mice after TBI. ATM inhibition also increased cell death in crypts at 4 h in Cdkn1a(p21CIP/WAF1)-/-, earlier than at 24 h in wild-type mice after TBI. In contrast, ATR inhibition decreased cell death in crypts in Cdkn1a(p21CIP/WAF1)-/- mice at 4 h after TBI. We conclude that ATM activity is essential for p21-dependent and p21-independent mechanisms that radioprotect intestinal crypts and that ATM inhibition promotes GI syndrome after TBI.
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Vendetti
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Leibowitz
authors.affiliation: DNA Damage Response Biology Area, Oncology IMED, AstraZeneca, Cambridge, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Barnes
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Schamus
authors.affiliation: Cancer Therapeutics Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Kiesel
authors.affiliation: Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
authors.forename: Shira
authors.initials: S
authors.lastname: Abberbock
authors.affiliation: Inova Schar Cancer Institute, Inova Center for Personalized Health, Falls Church, VA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Conrads
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: David Andy
authors.initials: DA
authors.lastname: Clump
authors.affiliation: DNA Damage Response Biology Area, Oncology IMED, AstraZeneca, Cambridge, UK.
authors.forename: Elaine
authors.initials: E
authors.lastname: Cadogan
authors.affiliation: DNA Damage Response Biology Area, Oncology IMED, AstraZeneca, Cambridge, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bakkenist
mesh_terms: D054508:Acute Radiation Syndrome / Q000188:drug therapy*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005260:Female; D016193:G1 Phase / Q000187:drug effects*; D005720:Gamma Rays / Q000009:adverse effects; D005767:Gastrointestinal Diseases / Q000188:drug therapy*; D007211:Indoles; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011833:Radiation Injuries, Experimental / Q000188:drug therapy*; D011837:Radiation-Protective Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides; D013454:Sulfoxides / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C000628947:AZ31 compound; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007211:Indoles; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D011837:Radiation-Protective Agents; D013449:Sulfonamides; D013454:Sulfoxides; C000611951:ceralasertib; D064007:Ataxia Telangiectasia Mutated Proteins