Wenjian Gong, Zhiqi Liao, Fan Xiong, Linghui Wang, Shen-Nan Shi, Mengshi Luo, Yuewen Zhang, Qiuyang Xu, Yuanyuan Wang, Yijie Wu, Li Zhu, Dong Kuang, Marilyne Labrie, Gordon B. Mills, Ding Ma, Dan Liu, Guang‐Nian Zhao, Qinglei Gao, Yong Fang
The combination of DNA damage response inhibitors (DDR inhibitors) has emerged as a promising strategy for anticancer therapy. Herein, we demonstrate that the combined administration of poly (ADP-ribose) polymerase (PARP) and ataxia telangiectasia and Rad3-related (ATR) inhibitors elicits PANoptosis across diverse cellular lineages, including non-cancerous cell populations. The induction of PANoptosis is dependent on mitotic entry and ZBP1-dependent PANoptosome (ZBP1-RIPK1-Caspase8-Caspase6). We identify the Aurora kinase B (AURKB) as the upstream regulator, essential for phosphorylation of ZBP1 which impacts ZBP1-dependent PANoptosome assembly and activation. The Trp53-/- Brca1-/- model of ID8 and two patient-derived xenograft (PDX) models further confirm the occurrence of PANoptosis following combination administration in vivo. The toxicity is mitigated in ZBP1-knockout mice. This study unveils a mechanism that dictates cell fate during DDR inhibitors-induced aberrant mitosis, emphasizing the critical balance between efficacy and safety in optimizing DDR inhibitors combination therapies. DNA damage response inhibitors are a promising cancer therapy. Here, the authors show that combined PARP and ATR inhibition triggers ZBP1-dependent PANoptosis in cancer and normal cells, revealing a mechanism to balance efficacy and toxicity in DDR inhibitor therapies.