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Mol Cancer Ther. 2017 Apr;16(4):566-577. doi: 10.1158/1535-7163.MCT-16-0378. Epub 2017 Jan 30.

AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells.

Min A1,2, Im SA3,2,4, Jang H1, Kim S1, Lee M1, Kim DK5, Yang Y1,4, Kim HJ1,6, Lee KH1,2,4, Kim JW1,7, Kim TY1,2,4, Oh DY1,2,4, Brown J8, Lau A9, O'Connor MJ9, Bang YJ1,2,4.

Author information

1
Cancer Research Institute, Seoul National University, Seoul, Korea.
2
Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
3
Cancer Research Institute, Seoul National University, Seoul, Korea. moisa@snu.ac.kr.
4
Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
5
Rice University, Houston, Texas.
6
Department of Internal Medicine, Chung Ang University College of Medicine, Seoul, Korea.
7
Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
8
AstraZeneca R&D Boston, Waltham, Massachusetts.
9
AstraZeneca UK Ltd., Macclesfield, Cheshire, United Kingdom.

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 an in vivo tumor 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.

PMID:
28138034
DOI:
10.1158/1535-7163.MCT-16-0378
[Indexed for MEDLINE]
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