Abstract 512: Inhibition of ATR enhances the anticancer activity of ciclopirox in triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is a deadly and difficult-to-treat cancer, partly due to drug resistance, which links to enhanced DNA damage response (DDR). Our previous studies have shown that ciclopirox olamine (CPX), an off-patent fungicide, inhibits cell proliferation and induces apoptosis of various tumor cells in vitro and in vivo. Mechanistically, this is partly associated with inhibition of the mTOR signaling in tumor cells. Meanwhile, CPX can induce DDR by activating the ATR-Chk1 pathway. AZD6738 (ATR inhibitor) is currently under clinical trials for treatment of solid tumors including TNBC. This study aimed at investigating whether AZD6738 can enhance the anticancer activity of CPX in TNBC. We found that AZD6738 potentiated CPX-induced inhibition of cell proliferation and induction of apoptosis in TNBC cells. CPX treatment decreased the levels of cyclins, CDKs and phospho-Rb and increased the levels of cleaved caspase-3 and γH2AX in TNBC cells, which could be strengthened by addition of AZD6738. In addition, we observed that the combined treatment with CPX/AZD6738 did not exhibit significant toxicity in nude mice, but inhibited tumor growth more potently than the single treatment with CPX or AZD6738 in MDA-MB-231 xenografts. The results indicate that inhibition of ATR with AZD6738 can potentiate the anticancer activity of CPX in TNBC cells in vitro and in vivo. Our finding suggests that combination of CPX and AZD6738 may represent a novel therapeutic approach for TNBC. Citation Format: Bing Cheng, Chinedum Okafor, Jehan Abdulsattar, Bolin Liu, Shile Huang. Inhibition of ATR enhances the anticancer activity of ciclopirox in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 512.