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Exp Cell Res. 2018 May 1;366(1):24-33. doi: 10.1016/j.yexcr.2018.03.006. Epub 2018 Mar 6.

ATM inhibition induces synthetic lethality and enhances sensitivity of PTEN-deficient breast cancer cells to cisplatin.

Author information

1
Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, China; Laboratory of Tumor Biotherapy and Cancer Center, West China Hospital, West China Hospital, Sichuan University, 17 People's South Road, Chengdu 610041, China.
2
Department of Functional Imaging, Sichuan Provincial Women's and Children's Hospital, 290# Sha Yan West Two Street, Jinyang Road, Wuhou District, Chengdu 610031, China.
3
Department of Abdominal Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 37, Guoxue Road, Chengdu 610041, Sichuan Province, China.
4
Laboratory of Tumor Biotherapy and Cancer Center, West China Hospital, West China Hospital, Sichuan University, 17 People's South Road, Chengdu 610041, China.
5
Department of Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Sichuan University, Chengdu 610041, China.
6
Laboratory of Tumor Biotherapy and Cancer Center, West China Hospital, West China Hospital, Sichuan University, 17 People's South Road, Chengdu 610041, China. Electronic address: yuanzhu@scu.edu.cn.

Abstract

PTEN deficiency often causes defects in DNA damage repair. Currently, effective therapies for breast cancer are lacking. ATM is an attractive target for cancer treatment. Previous studies suggested a synthetic lethality between PTEN and PARP. However, the synthetically lethal interaction between PTEN and ATM in breast cancer has not been reported. Moreover, the mechanism remains elusive. Here, using KU-60019, an ATM kinase inhibitor, we investigated ATM inhibition as a synthetically lethal strategy to target breast cancer cells with PTEN defects. We found that KU-60019 preferentially sensitizes PTEN-deficient MDA-MB-468 breast cancer cells to cisplatin, though it also slightly enhances sensitivity of PTEN wild-type breast cancer cells. The increased cytotoxic sensitivity is associated with apoptosis, as evidenced by flow cytometry and PARP cleavage. Additionally, the increase of DNA damage accumulation due to the decreased capability of DNA repair, as indicated by γ-H2AX and Rad51 foci, also contributed to this selective cytotoxicity. Mechanistically, compared with PTEN wild-type MDA-MB-231 cells, PTEN-deficient MDA-MB-468 cells have lower level of Rad51, higher ATM kinase activity, and display the elevated level of DNA damage. Moreover, these differences could be further enlarged by cisplatin. Our findings suggest that ATM is a promising target for PTEN-defective breast cancer.

KEYWORDS:

ATM inhibition; Breast cancer; Cisplatin; PTEN; Synthetic lethality

PMID:
29522753
DOI:
10.1016/j.yexcr.2018.03.006
[Indexed for MEDLINE]

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