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  3. Suppressing protein damage response to overcome multidrug resistance in cancer therapy

Suppressing protein damage response to overcome multidrug resistance in cancer therapy

  • Cell Discov. 2025 Sep 30;11(1):80. doi: 10.1038/s41421-025-00826-9.
Fangyuan Shao # 1 2 3,  Zongjie Li # 1 2,  Hao Xiao 4,  Yujun Chen 1,  Yuheng Zhang 1,  Ling Li 1 2,  Yuzhong Peng 1 2,  Xinyi Li 1,  Yuxing Hou 1,  Bo Li 5,  Xiangpeng Chu 1 2,  Maoxin Ran 1,  Dongyang Tang 1 2,  Xi Han 4,  Jiaxin Yao 6,  Cuiting Zhang 1 2,  Lijian Wang 1 2,  Haifeng Li 7,  Nan Shao 8,  Kai Miao 1 2 3,  Xiaoling Xu 1 2 3 9,  Yanxia Shi 10,  Changhua Zhang 11,  Jun Yan 12,  Ying Lin 13,  Chu-Xia Deng 14 15 16 17
Affiliations

Affiliations

  • 1 Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China.
  • 2 Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau SAR, China.
  • 3 MoE Frontiers Science Center for Precision Oncogene, University of Macau, Macau SAR, China.
  • 4 Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, Guangdong, China.
  • 5 Guangdong-Hong Kong-Macau University Joint Laboratory of Digestive Cancer Research, Guangdong Provincial Key Laboratory of Digestive Cancer Research, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China.
  • 6 Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
  • 7 Department of Medical Oncology, Sun Yet-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 8 Department of Breast Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 9 Zhuhai UM Science & Technology Research Institute, Hengqin, Zhuhai, Guangdong, China.
  • 10 Department of Medical Oncology, Sun Yet-sen University Cancer Center, Collaborative Innovation Center of Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
  • 11 Guangdong-Hong Kong-Macau University Joint Laboratory of Digestive Cancer Research, Guangdong Provincial Key Laboratory of Digestive Cancer Research, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, China. [email protected].
  • 12 Department of Colorectal Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China. [email protected].
  • 13 Department of Breast Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. [email protected].
  • 14 Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China. [email protected].
  • 15 Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau SAR, China. [email protected].
  • 16 MoE Frontiers Science Center for Precision Oncogene, University of Macau, Macau SAR, China. [email protected].
  • 17 Zhuhai UM Science & Technology Research Institute, Hengqin, Zhuhai, Guangdong, China. [email protected].
  • # Contributed equally.
PMID: 41027888 DOI: 10.1038/s41421-025-00826-9
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.

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