LAUSR

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 &ggr;‐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. HighlightsATM is a synthetically lethal target in breast cancer cells with PTEN defects.ATM inhibitor KU‐60019 preferentially sensitizes PTEN‐deficient breast cancer cells to cisplatin.The selective cytotoxicity results from the increase of DNA damage accumulation and the decreased capability of DNA repair.PTEN‐deficient MDA‐MB‐468 cells have lower level of Rad51, higher ATM kinase activity than PTEN wild‐type MDA‐MB‐231 cells.