2. Academic Validation
  3. Identification and characterization of Bufalin as a novel EGFR degrader

Identification and characterization of Bufalin as a novel EGFR degrader

  • Cancer Lett. 2025 Jul 28:623:217715. doi: 10.1016/j.canlet.2025.217715.
Yidi Tai 1,  Lulu Kong 2,  Yan Wang 3,  Dongyu Zhao 4,  Xu Chen 3,  Qingnan Wu 3,  Jia Hao 2,  Xi Wang 5,  Xingyang Liu 3,  Dongshao Chen 3,  Jinting Li 3,  Yuying Hu 3,  Weimin Zhang 6,  Cai-Hong Yun 7,  Qimin Zhan 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, Beijing Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China; Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Medical Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
  • 2 Department of Biophysics, Department of Integration of Chinese and Western Medicine, and Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China.
  • 3 State Key Laboratory of Molecular Oncology, Beijing Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China.
  • 4 Soochow University Cancer Institute, Suzhou, 215000, China.
  • 5 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Medical Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
  • 6 State Key Laboratory of Molecular Oncology, Beijing Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China; Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518107, China; Department of Oncology, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, China. Electronic address: zhangweimin@bjmu.edu.cn.
  • 7 Department of Biophysics, Department of Integration of Chinese and Western Medicine, and Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University, Beijing, 100191, China. Electronic address: yunch@hsc.pku.edu.cn.
  • 8 State Key Laboratory of Molecular Oncology, Beijing Key Laboratory of Carcinogenesis and Translational Research, Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing, 100021, China; Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518107, China; Department of Oncology, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, China; Soochow University Cancer Institute, Suzhou, 215000, China. Electronic address: zhanqimin@bjmu.edu.cn.
PMID: 40220852 DOI: 10.1016/j.canlet.2025.217715
Abstract

Esophageal squamous cell carcinoma (ESCC) stands out as a common Cancer type worldwide, characterized by its notably high rates of occurrence and mortality. The epidermal growth factor receptor (EGFR) is one of the main targets for Cancer treatment as it is one of the genes whose expression is often altered by overexpression, amplification, and mutation in a variety of solid tumors. Substantial efforts have been made to develop EGFR-targeted therapeutic agents, including monoclonal antibodies and tyrosine kinase inhibitors (TKIs). However, these agents exhibited limited efficacy due to the emergence of acquired resistance. Therefore, novel treatment strategies targeting EGFR are urgently needed. Recent studies have identified a few natural compounds that can efficiently inhibit EGFR, indicating that natural products may be potential sources for the development of new EGFR inhibitors. Here, using the Drug Affinity Responsive Target Stability (DARTS) assay combined with liquid chromatography/tandem mass spectrometry analysis, co-crystal method, we discovered that Bufalin directly interacts with EGFR and causes EGFR endocytosis and degradation in the lysosome. Moreover, Bufalin exhibits superior anti-tumor activity compared with another EGFR TKIs. Our study identified Bufalin as the first natural small-molecule EGFR degrader, which suppresses EGFR signaling by inducing the degradation of EGFR via the endosome-lysosome pathway.

Keywords

ATP competitive inhibitor; Bufalin; Epidermal growth factor receptor; Esophageal square carcinoma; Protein degradation; Target identification.

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