Abstract 2830: Aurora kinase B phosphorylates ZBP1 to drive PANoptosis following treatment with a combination of PARP and ATR inhibitors

Background: The combination of DNA damage response inhibitors (DDRis) to induce unrepaired DNA damage entry into mitosis prematurely has emerged as a promising strategy for anticancer therapy. However, the efficacy is often limited by their tolerability due to associated toxicities. Method & Result: Here we demonstrate that combining poly (ADP-ribose) polymerase (PARP) and ATR inhibitors induces PANoptosis in both cancer and non-cancer cells as a result of abnormal mitotic progression. This is highly dependent on CDK1 activity. Furthermore, ZBP1-dependent PANoptosome (ZBP1-RIPK1-CASP8-CASP6) mediated PARP and ATR inhibitors combination therapy induced PANoptosis. Further exploration revealed that the kinase activity of aurora kinase B (AURKB) was essential for ZBP1-mediated PANoptosis following the treatment. ZBP1 could be phosphorylated by AURKB during mitosis, and phosphorylated ZBP1 subsequently facilitates the assembly and activation of PANoptosome. Finally, our findings were validated in an ovarian cancer patient-derived xenograft (PDX) model in which PARPi and ATRi combination induced PANoptosis in both tumor and normal tissue Importantly, the toxicity to normal tissues was mitigated in ZBP1-knockout mice. Conclusion: Overall, these results suggest that phosphorylation of ZBP1 by AURKB triggers the activation of ZBP1-dependent PANoptosome after treatment with PARPi and ATRi combination, leading to cell-intrinsic antineoplastic activity and toxicity. Our study elucidates the specific mechanisms underlying cell fate determination during aberrant mitosis progression resulting from PARPi and ATRi combination therapy. These findings provide a theoretical foundation for understanding their anticancer effects and toxicity, crucial for optimizing the use of DDRis combination approaches in the clinic. Citation Format: Wenjian Gong, Zhiqi Liao, Shennan Shi, Fan Xiong, Mengshi Luo, Yuewen Zhang, Qiuyang Xu, Yijie Wu, Linghui Wang, Li Zhu, Dong Kuang, Marilyne Labrie, Xuejiao Zhao, Gordon B Mills, Ding Ma, Guangnian Zhao, Qinglei Gao, Yong Fang. Aurora kinase B phosphorylates ZBP1 to drive PANoptosis following treatment with a combination of PARP and ATR inhibitors [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 2830.