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<p>Multidrug resistance is a significant barrier in cancer therapy largely due to poorly understood regulatory mechanisms. Here we reveal that certain anticancer drugs can bind to newly synthesized proteins prior to reaching their canonical targets, resulting in various forms of protein damage. This binding disrupts protein functions, particularly those of mitochondrial proteins, resulting in substantial cytotoxicity. The protein damage is further exacerbated by mitochondrial reactive oxygen species generated as a consequence of the initial damage, creating a positive feedback loop. In response, cancer cells rapidly initiate a chain of events, which we term the <Emphasis Type="Underline">P</Emphasis>rotein <Emphasis Type="Underline">D</Emphasis>amage <Emphasis Type="Underline">R</Emphasis>esponse (PDR). This includes damage recognition primarily mediated by protein ubiquitination and subsequent damage clearance via the proteasome system. Notably, patients with advanced, drug-resistant metastatic breast or colon cancers exhibit elevated proteasome activity. In an effort to predict drug resistance, we developed a sensitive kit for detecting proteasome levels, enabling the identification and subtyping of patients with high proteasome activity to support tailored therapeutic strategies. Using a three-dimensional tumor slice culture-based drug sensitivity assay and an investigator-initiated clinical trial, we demonstrate that three clinically approved proteasome inhibitors effectively overcome multidrug resistance in colon and breast cancer patients with elevated proteasome activity.</p>

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Suppressing protein damage response to overcome multidrug resistance in cancer therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月30日

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  • Fangyuan Shao,
  • Zongjie Li,
  • Hao Xiao,
  • Yujun Chen,
  • Yuheng Zhang,
  • Ling Li,
  • Yuzhong Peng,
  • Xinyi Li,
  • Yuxing Hou,
  • Bo Li,
  • Xiangpeng Chu,
  • Maoxin Ran,
  • Dongyang Tang,
  • Xi Han,
  • Jiaxin Yao,
  • Cuiting Zhang,
  • Lijian Wang,
  • Haifeng Li,
  • Nan Shao,
  • Kai Miao,
  • Xiaoling Xu,
  • Yanxia Shi,
  • Changhua Zhang,
  • Jun Yan,
  • Ying Lin,
  • Chu-Xia Deng

摘要

Multidrug resistance is a significant barrier in cancer therapy largely due to poorly understood regulatory mechanisms. Here we reveal that certain anticancer drugs can bind to newly synthesized proteins prior to reaching their canonical targets, resulting in various forms of protein damage. This binding disrupts protein functions, particularly those of mitochondrial proteins, resulting in substantial cytotoxicity. The protein damage is further exacerbated by mitochondrial reactive oxygen species generated as a consequence of the initial damage, creating a positive feedback loop. In response, cancer cells rapidly initiate a chain of events, which we term the Protein Damage Response (PDR). This includes damage recognition primarily mediated by protein ubiquitination and subsequent damage clearance via the proteasome system. Notably, patients with advanced, drug-resistant metastatic breast or colon cancers exhibit elevated proteasome activity. In an effort to predict drug resistance, we developed a sensitive kit for detecting proteasome levels, enabling the identification and subtyping of patients with high proteasome activity to support tailored therapeutic strategies. Using a three-dimensional tumor slice culture-based drug sensitivity assay and an investigator-initiated clinical trial, we demonstrate that three clinically approved proteasome inhibitors effectively overcome multidrug resistance in colon and breast cancer patients with elevated proteasome activity.