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<p>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 <i>Trp53</i><sup>-/-</sup> <i>Brca1</i><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.</p>

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Aurora kinase B phosphorylates ZBP1 to drive PANoptosis following treatment with PARP and ATR inhibitors combination

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月27日

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  • Wenjian Gong,
  • Zhiqi Liao,
  • Fan Xiong,
  • Linghui Wang,
  • Shennan 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

摘要

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.