Department of Pharmacology, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu, 610041, China.
Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
Chem Biol Interact. 2023 Nov 1;385:110740. doi: 10.1016/j.cbi.2023.110740. Epub 2023 Oct 5.
Targeting replication stress response is currently emerging as new therapeutic strategy for cancer treatment, based on monotherapy and combination approaches. As a key sensor in response to DNA damage, ataxia telangiectasia and rad3-related (ATR) kinase has become a potential therapeutic target as tumor cells are to rely heavily on ATR for survival. The tumor suppressor phosphatase and tensin homolog (PTEN) plays a crucial role in maintaining chromosome integrity. Although ATR inhibition was recently confirmed to show a synergistic inhibitory effect in PTEN-deficient triple-negative breast cancer cells, the molecular mechanism needs to be further elucidated. Additionally, whether the PTEN-deficient breast cancer cells are more preferentially sensitized than PTEN-wild type breast cancer cells to cisplatin plus ATR inhibitor remains unanswered. We demonstrate PTEN dysfunction promotes the killing effect of ATR blockade through the use of RNA interference for PTEN and a highly selective ATR inhibitor VE-821, and certify that VE-821 (1.0 μmol/L) aggravates cytotoxicity of cisplatin on breast cancer cells, especially PTEN-null MDA-MB-468 cells which show more chemoresistance than PTEN-expressing MDA-MB-231 cells. The co-treatment with VE-821 and cisplatin significantly reduced cell viability and proliferative capacity compared with cisplatin mono-treatment (P < 0.05). The increased cytotoxic activity is tied to the enhanced poly (ADP-ribose) polymerase (PARP) cleavage and consequently cell death due to the decrease in phosphorylation levels of checkpoint kinases 1 and 2 (CHK1/2), the reduction of radiation sensitive 51 (RAD51) foci and the increase in phosphorylation of the histone variant H2AX (γ-H2AX) foci (P < 0.05) as well. Together, these findings suggest combination therapy of ATR inhibitor and cisplatin may offer a potential therapeutic strategy for breast tumors.
靶向复制应激反应目前正成为癌症治疗的新策略，包括单药治疗和联合治疗。作为对 DNA 损伤的关键传感器，共济失调毛细血管扩张症和 rad3 相关（ATR）激酶已成为一种潜在的治疗靶点，因为肿瘤细胞严重依赖 ATR 存活。肿瘤抑制因子磷酸酶和张力蛋白同源物（PTEN）在维持染色体完整性方面起着至关重要的作用。尽管最近证实 ATR 抑制在 PTEN 缺陷型三阴性乳腺癌细胞中显示出协同抑制作用，但仍需要进一步阐明其分子机制。此外，PTEN 缺陷型乳腺癌细胞是否比 PTEN 野生型乳腺癌细胞对顺铂加 ATR 抑制剂更敏感，这一问题仍未得到解答。我们通过使用 RNA 干扰 PTEN 和高度选择性的 ATR 抑制剂 VE-821 证明了 PTEN 功能障碍通过 ATR 阻断促进杀伤作用，并证明 VE-821（1.0 μmol/L）加重了顺铂对乳腺癌细胞的细胞毒性，特别是对 PTEN 缺失的 MDA-MB-468 细胞，其对化疗的耐药性高于表达 PTEN 的 MDA-MB-231 细胞。与顺铂单药治疗相比，VE-821 与顺铂联合治疗显著降低了细胞活力和增殖能力（P < 0.05）。由于检查点激酶 1 和 2（CHK1/2）的磷酸化水平降低，辐射敏感 51（RAD51）焦点减少，组蛋白变体 H2AX（γ-H2AX）焦点的磷酸化增加，导致细胞毒性增强（P < 0.05）。综上所述，这些发现表明 ATR 抑制剂和顺铂的联合治疗可能为乳腺癌提供一种潜在的治疗策略。
