title: AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells.
abstract: Ataxia telangiectasia and Rad3-related (ATR) can be considered an attractive target for cancer treatment due to its deleterious effect on cancer cells harboring a homologous recombination defect. The aim of this study was to investigate the potential use of the ATR inhibitor, AZD6738, to treat gastric cancer.In SNU-601 cells with dysfunctional ATM, AZD6738 treatment led to an accumulation of DNA damage due to dysfunctional RAD51 foci formation, S phase arrest, and caspase 3-dependent apoptosis. In contrast, SNU-484 cells with functional ATM were not sensitive to AZD6738. Inhibition of ATM in SNU-484 cells enhanced AZD6738 sensitivity to a level comparable with that observed in SNU-601 cells, showing that activation of the ATM-Chk2 signaling pathway attenuates AZD6738 sensitivity. In addition, decreased HDAC1 expression was found to be associated with ATM inactivation in SNU-601 cells, demonstrating the interaction between HDAC1 and ATM can affect sensitivity to AZD6738. Furthermore, in anin vivotumor xenograft mouse model, AZD6738 significantly suppressed tumor growth and increased apoptosis.These findings suggest synthetic lethality between ATR inhibition and ATM deficiency in gastric cancer cells. Further clinical studies on the interaction between AZD 6738 and ATM deficiency are warranted to develop novel treatment strategies for gastric cancer.Mol Cancer Ther; 16(4); 566-77. ©2017 AACR.
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
authors.forename: Ahrum
authors.initials: A
authors.lastname: Min
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea. moisa@snu.ac.kr.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Hyemin
authors.initials: H
authors.lastname: Jang
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Seongyeong
authors.initials: S
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Miso
authors.initials: M
authors.lastname: Lee
authors.affiliation: Rice University, Houston, Texas.
authors.forename: Debora Keunyoung
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yaewon
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Department of Internal Medicine, Chung Ang University College of Medicine, Seoul, Korea.
authors.forename: Hee-Jun
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Kyung-Hun
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.affiliation: AstraZeneca R&D Boston, Waltham, Massachusetts.
authors.forename: Jeff
authors.initials: J
authors.lastname: Brown
authors.affiliation: AstraZeneca UK Ltd., Macclesfield, Cheshire, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Lau
authors.affiliation: AstraZeneca UK Ltd., Macclesfield, Cheshire, United Kingdom.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: O'Connor
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency*; D053148:Caspase 3 / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D064447:Checkpoint Kinase 2 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056284:Histone Deacetylase 1 / Q000235:genetics; D006801:Humans; D007211:Indoles; D051379:Mice; D009025:Morpholines; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics; D013449:Sulfonamides; D013454:Sulfoxides / Q000008:administration & dosage* / Q000494:pharmacology; D000072020:Synthetic Lethal Mutations / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D009025:Morpholines; D011743:Pyrimidines; D013449:Sulfonamides; D013454:Sulfoxides; C000611951:ceralasertib; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; C505407:CASP3 protein, human; D053148:Caspase 3; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1