2. Academic Validation
  3. Erdafitinib inhibits the tumorigenicity of MDA-MB-231 triple-negative breast cancer cells by inducing TRIM25/ubiquitin-dependent degradation of FGFR4

Erdafitinib inhibits the tumorigenicity of MDA-MB-231 triple-negative breast cancer cells by inducing TRIM25/ubiquitin-dependent degradation of FGFR4

  • Breast Cancer Res. 2025 Jul 9;27(1):128. doi: 10.1186/s13058-025-02086-7.
Qing Luo # 1 2,  Li Zhang # 2,  Yue Hao 3,  Chunwei Xu 4,  Xiaojia Wang 5,  Zhen Jia 6,  Xiandong Xie 7,  Zhihong Huang 8 9,  Xiaomin Gao 1 2,  Yu Chen 2,  Xue Zhu 8 9,  Jing Fang 8 9,  Ke Wang 10 11,  Yongxiang Yin 12 13
Affiliations

Affiliations

  • 1 Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu Province, China.
  • 2 Wuxi Maternity and Child Health Care Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi, 214002, Jiangsu Province, China.
  • 3 Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, People's Republic of China.
  • 4 Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, People's Republic of China.
  • 5 Department of Breast Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, People's Republic of China.
  • 6 Department of Clinical Laboratory, Haidong No. 2 People's Hospital, Haidong, 810799, China.
  • 7 School of Clinical Medicine, Youjiang Medical University for Nationalities, Baise, 533000, Guangxi, China.
  • 8 NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu Province, China.
  • 9 Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
  • 10 NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu Province, China. wangke@jsinm.org.
  • 11 Department of Radiopharmaceuticals, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China. wangke@jsinm.org.
  • 12 Wuxi School of Medicine, Jiangnan University, Wuxi, 214122, Jiangsu Province, China. yinyrh@jiangnan.edu.cn.
  • 13 Wuxi Maternity and Child Health Care Hospital, Affiliated Women's Hospital of Jiangnan University, Wuxi, 214002, Jiangsu Province, China. yinyrh@jiangnan.edu.cn.
  • # Contributed equally.
PMID: 40635078 DOI: 10.1186/s13058-025-02086-7
Abstract

Triple-negative breast Cancer (TNBC) is the most malignant subtype of breast Cancer (BC), characterized by limited treatment options and poor clinical outcomes. Aberrant FGFR signaling has been implicated in TNBC; however, the therapeutic potential of targeting FGFRs for TNBC treatment remains unclear. This study investigated the anti-cancer activity of the selective pan-FGFR inhibitor Erdafitinib and its underlying mechanisms using both in vitro and in vivo models. The results demonstrated that Erdafitinib suppressed TNBC tumorigenicity by promoting FGFR1/4 degradation, generating Reactive Oxygen Species (ROS), inducing DNA damage, and ultimately triggering cell death. Mechanistic analyses revealed that Erdafitinib facilitated FGFR1/4 degradation through ubiquitination, enhanced interaction between TRIM25 and FGFR1/4, and subsequent lysosomal degradation. Furthermore, RNA-seq data from the TCGA and GEO databases, along with paired tumor tissues from TNBC patients, indicated that FGFR4 was significantly upregulated in TNBC. Notably, co-knockdown of FGFR1 and FGFR4 induced cytotoxicity in MDA-MB-231 cells, highlighting the therapeutic relevance of FGFR1/4 degradation by Erdafitinib in TNBC. These findings provide novel insights into the mechanisms underlying the anti-cancer efficacy of Erdafitinib, supporting its potential as a promising therapeutic agent for TNBC.

Keywords

Biomarker; Erdafitinib; FGFR1/4; TNBC; TRIM25; Ubiquitination.

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