Related Experiment Video
Updated: May 21, 2025
An Orthotopic Bladder Cancer Model for Gene Delivery Studies
Published on: December 1, 2013
Targeting COPA to Enhance Erdafitinib Sensitivity in FGFR-Altered Bladder Cancer
Huayuan Zhao1, Xincheng Gao1, Yangkai Jiang2
1Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Abstract:
Fibroblast growth factor receptor (FGFR) family aberrations are common in urothelial cancer. The FGFR tyrosine kinase inhibitor erdafitinib has been approved for locally advanced or metastatic urothelial cancer with FGFR2/3 alterations. Despite the initial efficacy of erdafitinib, resistance cannot be avoided. The molecular mechanisms underlying erdafitinib resistance have not been well investigated. Here, genome-wide CRISPR screen is performed and coatomer protein complex subunit α (COPA) is identified as a key target to enhance erdafitinib sensitivity. Functionally, the deficiency of COPA reduces the proliferation of FGFR-altered bladder cancer cells upon erdafitinib treatment. Mechanistically, COPA knockout increases the degradation of leucine-rich pentatricopeptide repeat containing (LRPPRC) protein, leading to reduced inhibitor of DNA binding 3 (ID3) mRNA stability in an m6A-dependent manner. Collectively, these findings reveal a novel mechanism of erdafitinib resistance, providing a potential therapeutic target for FGFR-altered bladder cancer.
Insights
Coatomer protein complex subunit α (COPA) deficiency enhances erdafitinib sensitivity in FGFR-altered bladder cancer. This finding reveals a novel resistance mechanism and a potential therapeutic target for urothelial cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Fibroblast growth factor receptor (FGFR) aberrations are prevalent in urothelial cancer.
- Erdafitinib, an FGFR tyrosine kinase inhibitor, is approved for advanced urothelial cancer with FGFR2/3 alterations.
- Mechanisms of erdafitinib resistance remain incompletely understood.
Purpose of the Study:
- To investigate the molecular mechanisms of erdafitinib resistance in urothelial cancer.
- To identify novel therapeutic targets for enhancing erdafitinib sensitivity.
Main Methods:
- Genome-wide CRISPR screening was employed to identify genetic modifiers of erdafitinib sensitivity.
- Functional assays were conducted to assess the role of identified targets in cancer cell proliferation.
- Molecular mechanisms involving protein degradation and mRNA stability were investigated.
Main Results:
- Coatomer protein complex subunit α (COPA) was identified as a key target that enhances erdafitinib sensitivity.
- COPA deficiency reduced the proliferation of FGFR-altered bladder cancer cells treated with erdafitinib.
- COPA knockout led to increased degradation of LRPPRC, reducing ID3 mRNA stability in an m6A-dependent manner.
Conclusions:
- This study reveals a novel mechanism of erdafitinib resistance mediated by COPA.
- Targeting COPA presents a potential therapeutic strategy for overcoming erdafitinib resistance in FGFR-altered bladder cancer.
More Related Videos
08:52Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
11:02Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
