Aurora kinase B phosphorylates ZBP1 to drive PANoptosis following treatment with PARP and ATR inhibitors combination
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<sup>-/-</sup> Brca1<sup>-/-</sup> 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.
Authors
- Gordon Brent Mills (ORCID: https://orcid.org/0000-0002-0144-9614)
- Dan Liu (ORCID: https://orcid.org/0000-0002-9971-2264)
- Qinglei Gao (ORCID: https://orcid.org/0000-0002-9448-3423)
- Fan Xiong (ORCID: https://orcid.org/0000-0002-1144-0912)
- Yong Fang (ORCID: https://orcid.org/0000-0003-3412-8208)
- Dong Kuang (ORCID: https://orcid.org/0000-0002-8455-3379)
- Guang‐Nian Zhao (ORCID: https://orcid.org/0000-0002-3112-7595)
- Wenjian Gong (ORCID: https://orcid.org/0009-0001-3247-1224)
- Linghui Wang
- Marilyne Labrie (ORCID: https://orcid.org/0000-0003-3957-5533)
- Shen-Nan Shi
- Qiuyang Xu (ORCID: https://orcid.org/0000-0001-7132-1707)
- Li Zhu (ORCID: https://orcid.org/0000-0002-5988-5371)
- Zhiqi Liao
- Mengshi Luo
- Ding Ma (ORCID: https://orcid.org/0000-0003-3317-7016)
- Yijie Wu (ORCID: https://orcid.org/0009-0004-3599-2545)
- Yuanyuan Wang (ORCID: https://orcid.org/0000-0003-4987-3892)
- Yuewen Zhang (ORCID: https://orcid.org/0000-0003-1864-769X)
Institutions
- Tongji University (CN)
- Université de Sherbrooke (CA)
- Oregon Health & Science University (US)
- Tongji Hospital (CN)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-27
- DOI
- https://doi.org/10.1038/s41467-025-66591-1
- Primary Topic
- Microtubule and mitosis dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00