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.
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.
Exp Cell Res. 2018 May 1;366(1):24-33. doi: 10.1016/j.yexcr.2018.03.006. Epub 2018 Mar 6.
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.
PTEN 缺失通常会导致 DNA 损伤修复缺陷。目前，针对乳腺癌缺乏有效的治疗方法。ATM 是癌症治疗的一个有吸引力的靶点。先前的研究表明，PTEN 和 PARP 之间存在合成致死性。然而，PTEN 和 ATM 之间在乳腺癌中的合成致死相互作用尚未被报道。此外，其机制仍不清楚。在这里，我们使用 ATM 激酶抑制剂 KU-60019，研究了 ATM 抑制作为一种针对具有 PTEN 缺陷的乳腺癌细胞的合成致死策略。我们发现，KU-60019 优先使 PTEN 缺失的 MDA-MB-468 乳腺癌细胞对顺铂敏感，尽管它也略微增强了 PTEN 野生型乳腺癌细胞的敏感性。细胞毒性敏感性的增加与凋亡有关，这可以通过流式细胞术和 PARP 切割来证明。此外，由于 DNA 修复能力下降导致的 DNA 损伤积累的增加，如 γ-H2AX 和 Rad51 焦点所示，也有助于这种选择性细胞毒性。在机制上，与 PTEN 野生型 MDA-MB-231 细胞相比，PTEN 缺失的 MDA-MB-468 细胞具有更低水平的 Rad51、更高的 ATM 激酶活性，并显示出更高水平的 DNA 损伤。此外，这些差异可以通过顺铂进一步扩大。我们的研究结果表明，ATM 是 PTEN 缺陷型乳腺癌的一个有前途的靶点。
