Suppressing protein damage response to overcome multidrug resistance in cancer therapy

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.

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Publication Details

Journal
Cell Discovery
Published
2025-09-30
DOI
https://doi.org/10.1038/s41421-025-00826-9
Citations
2
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
1.61

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article

Suppressing protein damage response to overcome multidrug resistance in cancer therapy

Cuiting Zhang, Xiaoling Xu, Bo Li, Chu‐Xia Deng et al.
2 citations
Cell Discovery
Ubiquitin and proteasome pathways
1.61
article

Suppressing protein damage response to overcome multidrug resistance in cancer therapy

Cuiting Zhang, Xiaoling Xu, Bo Li, Chu‐Xia Deng, Yuheng Zhang, Yuzhong Peng, Xingsi Han, Hao Xiao, Jiaxin Yao, Fangyuan Shao, Yanxia Shi, Kai Miao, Xiangpeng Chu, Nan Shao, Xinyi Li, Haifeng Li, Lei Li, Changhua Zhang, Ying Lin, Zongjie Li, Yujun Chen, Lijian Wang, Yanming Hou, Dongyang Tang, Maoxin Ran, Jun Yan
article en
2 citations

Abstract

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.

Cell DiscoveryVol. 11(1)
Fujian Medical University (CN), Sun Yat-sen University (CN), University of Macau (MO), Guangdong Polytechnic of Science and Technology (CN), The Seventh Affiliated Hospital of Sun Yat-sen University (CN), Guangdong Academy of Agricultural Sciences (CN), The First Affiliated Hospital, Sun Yat-sen University (CN), Sun Yat-sen University Cancer Center (CN), Union Hospital (CN), Zhuhai Institute of Advanced Technology (CN), City University of Macau (MO)
National Natural Science Foundation of China, Universidade de Macau, Fundo para o Desenvolvimento das Ciências e da Tecnologia, Basic and Applied Basic Research Foundation of Guangdong Province
Openalex Percentile: Top 15%
Ubiquitin and proteasome pathways
1.61
DOIOpen Access PDFOpenAlex
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