title: Pharmacologic inhibition of ATR and ATM offers clinically important distinctions to enhancing platinum or radiation response in ovarian, endometrial, and cervical cancer cells.
abstract: OBJECTIVE
  Significant reductions in gynecologic (GYN) cancer mortality and morbidity require treatments that prevent and reverse resistance to chemotherapy and radiation. The objective of this study was to determine if pharmacologic inhibition of key DNA damage response kinases in GYN cancers would enhance cell killing by platinum-based chemotherapy and radiation.
  
  
  METHODS
  A panel of human ovarian, endometrial and cervical cancer cell lines were treated with platinum drugs or ionizing radiation (IR) along with small molecule pharmacological kinase inhibitors of Ataxia telangiectasia mutated (ATM) and ATM and Rad-3-related (ATR).
  
  
  RESULTS
  Pharmacologic inhibition of ATR significantly enhanced platinum drug response in all GYN cancer cell lines tested, whereas inhibition of ATM did not enhance the response to platinum drugs. Co-inhibition of ATM and ATR did not enhance platinum kill beyond that observed by inhibition of ATR alone. By contrast, inhibiting either ATR or ATM enhanced the response to IR in all GYN cancer cells, with further enhancement achieved with co-inhibition.
  
  
  CONCLUSIONS
  These studies highlight actionable mechanisms operative in GYN cancer cells with potential to maximize response of platinum agents and radiation in newly diagnosed as well as recurrent gynecologic cancers.
authors.affiliation: Women's Health Integrated Research Center at Inova Health System, Department of Defense Gynecologic Cancer Center of Excellence, Annandale, VA 22003, USA.
authors.forename: Pang-ning
authors.initials: PN
authors.lastname: Teng
authors.affiliation: Women's Health Integrated Research Center at Inova Health System, Department of Defense Gynecologic Cancer Center of Excellence, Annandale, VA 22003, USA.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Bateman
authors.affiliation: Women's Health Integrated Research Center at Inova Health System, Department of Defense Gynecologic Cancer Center of Excellence, Annandale, VA 22003, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Darcy
authors.affiliation: Women's Health Integrated Research Center at Inova Health System, Department of Defense Gynecologic Cancer Center of Excellence, Annandale, VA 22003, USA; Gynecologic Oncology Service, Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, Bethesda, MD, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Hamilton
authors.affiliation: Women's Health Integrated Research Center at Inova Health System, Department of Defense Gynecologic Cancer Center of Excellence, Annandale, VA 22003, USA; Department of Obstetrics and Gynecology, Inova Fairfax Hospital, Fairfax, VA, USA.
authors.forename: George Larry
authors.initials: GL
authors.lastname: Maxwell
authors.affiliation: Department of Radiation Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bakkenist
authors.affiliation: Women's Health Integrated Research Center at Inova Health System, Department of Defense Gynecologic Cancer Center of Excellence, Annandale, VA 22003, USA. Electronic address: conrads@whirc.org.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Conrads
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology* / Q000627:therapeutic use; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy* / Q000201:enzymology / Q000532:radiotherapy*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology
chemical_list: C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C000598436:ETP-46464; D009025:Morpholines; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011753:Pyrones; D011804:Quinolines; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D002945:Cisplatin
keywords: ATM; ATR; Cisplatin resistance; DNA damage repair response; Gynecologic cancer; Ionizing radiation