Abstract 6783: ATM inhibitor AZD1390 sensitizes nasopharyngeal cancer cells to chemotherapy by reversing chemotherapy-induced autophagy

Abstract Background: Nasopharyngeal carcinoma (NPC) is renowned for its high sensitivity towards chemotherapeutic agents. Nonetheless, chemoresistance remains a major reason for treatment failure in NPC. Ataxia telangiectasia mutated (ATM) has a diverse role in cellular homeostasis, regulating DNA damage response, apoptosis and autophagy. Pharmacological inhibition of ATM is hypothesized to disrupt the DNA damage response towards chemotherapy-induced DNA breaks, which in turn enhances the chemosensitivity of tumor cells. However, given the multifaceted role of autophagy in various cell death mechanisms, the interplay between autophagy and DNA damage response remains elusive. Therefore, we aim to investigate the therapeutical potential of ATM inhibitor AZD1390 in NPC via the regulation of autophagy. Methods: Antitumor effects of AZD1390 in conjunction with cisplatin were evaluated on two NPC cell lines, NPC43 and C17. Cell lines were pretreated with AZD1390 for 2 hours prior to the administration of cisplatin for 72 hours. We assessed the anti-proliferative effects through annexin V/propidium iodide, CellTiter-Glo, XTT, clonogenic assay and cell cycle analysis. The mechanism of action and autophagic activity upon treatment of AZD1390 were examined by means of a combination of mass spectrometry, western blot, autophagy detection kit and immunofluorescence approaches. Results: Cisplatin treatment with concurrent AZD1390 pretreatment enhanced the anti-proliferative effect in NPC cell lines compared to cisplatin alone. XTT, cell cycle analysis and colony formation assay revealed a reduced tumor cell clonogenicity and proliferation with an accumulation of cell population in the G0/G1 phase upon the combined treatment. However, no significant changes were observed in terms of apoptosis and necrosis. We observed that cisplatin treatment alone induced autophagy, whereas, in conjunction with AZD1390 pretreatment, the cisplatin-induced autophagy was reversed, indicated by the reduced autophagic activity detected by autophagy detection kit and the increased colocalization of LC-3 and lysosome in immunofluorescent staining. These findings were further supported by our mass spectrometry data that the mTOR signaling pathway, indicative of autophagy inhibition, was significantly enriched in cells treated with AZD1390 in combination with cisplatin as compared to cisplatin alone. Conclusions: Our findings demonstrated that AZD1390 augments the sensitivity of NPC cell lines to chemotherapy through the reversion of chemotherapy-induced autophagy. Therefore, AZD1390 could potentially serve as a chemosensitizer in NPC treatment. Citation Format: Syrus Pak Hei Lai, Ngar Woon Kam, Victor Ho-Fun Lee. ATM inhibitor AZD1390 sensitizes nasopharyngeal cancer cells to chemotherapy by reversing chemotherapy-induced autophagy [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 6783.