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<p>Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and lethal malignancies, with limited treatment options and poor clinical outcomes. KU-57788, a selective inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), has shown promise in cancer therapy when combined with radiotherapy and chemotherapy. However, its therapeutic potential and underlying mechanisms in ATC remain unclear. In this study, we demonstrate that KU-57788 exerts potent anti-ATC activity both in vitro and in vivo by inducing DNA damage and triggering mitotic catastrophe. Unexpectedly, we identify a novel mechanism whereby KU-57788 directly binds to and activates dynamin-related protein 1 (DRP1), leading to excessive mitochondrial fission and fragmentation. This process is accompanied by the protective activation of the NRF2/SLC7A11/GSH axis, which mitigates the cytotoxic effects of KU-57788. Notably, pharmacological induction of ferroptosis or cystine depletion effectively synergizes with ATC cells to KU-57788, overcoming resistance and promoting ferroptosis. Collectively, our findings highlight the therapeutic potential of KU-57788 in ATC while revealing an intrinsic resistance mechanism mediated by DRP1 activation and the potential involvement of the NRF2/SLC7A11/GSH axis. More importantly, we provide strong evidence that combining KU-57788 with ferroptosis inducers significantly enhances its anticancer efficacy, offering a promising therapeutic strategy for ATC.</p><p></p>

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Direct coupling and protective activation of DRP1 by the DNA-PKcs inhibitor KU-57788 synergizes with ferroptosis in anaplastic thyroid cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月28日

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  • Lingling Ding,
  • Changtian Yin,
  • Yehao Guo,
  • Qiang Geng,
  • Wanwan He,
  • Yawen Guo,
  • Jinpeng Wen,
  • Aoni Zhou,
  • Jieyu Luo,
  • Xinxin Ren,
  • Jiajie Xu,
  • Renhao Ou,
  • Ruonan Jia,
  • Jiaxin Tian,
  • Yuchen Wang,
  • Yefeng Cai,
  • Wenzhen Wang,
  • Haifeng Xu,
  • Lei Zhu,
  • Minghua Ge,
  • Guowan Zheng,
  • Chuanming Zheng

摘要

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and lethal malignancies, with limited treatment options and poor clinical outcomes. KU-57788, a selective inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), has shown promise in cancer therapy when combined with radiotherapy and chemotherapy. However, its therapeutic potential and underlying mechanisms in ATC remain unclear. In this study, we demonstrate that KU-57788 exerts potent anti-ATC activity both in vitro and in vivo by inducing DNA damage and triggering mitotic catastrophe. Unexpectedly, we identify a novel mechanism whereby KU-57788 directly binds to and activates dynamin-related protein 1 (DRP1), leading to excessive mitochondrial fission and fragmentation. This process is accompanied by the protective activation of the NRF2/SLC7A11/GSH axis, which mitigates the cytotoxic effects of KU-57788. Notably, pharmacological induction of ferroptosis or cystine depletion effectively synergizes with ATC cells to KU-57788, overcoming resistance and promoting ferroptosis. Collectively, our findings highlight the therapeutic potential of KU-57788 in ATC while revealing an intrinsic resistance mechanism mediated by DRP1 activation and the potential involvement of the NRF2/SLC7A11/GSH axis. More importantly, we provide strong evidence that combining KU-57788 with ferroptosis inducers significantly enhances its anticancer efficacy, offering a promising therapeutic strategy for ATC.