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Background <p>Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) effectively treat metastatic colorectal cancer (CRC); however, predicting response to these therapies remains challenging. Here, we aimed to identify key regulators of EGFR internalization as predictive biomarkers for anti-EGFR mAb therapy in CRC.</p> Methods <p>CRC cell lines were treated with cetuximab and EGFR internalization was analyzed using siRNA knockdowns, inhibitors, and proteomic analyses. Key proteins mediating cetuximab-bound EGFR internalization were identified through immunoprecipitation and tandem mass spectrometry and validated using RT-PCR, co-immunoprecipitation, immunofluorescence, cell viability, and apoptosis assays. Immunohistochemistry was performed to correlate findings with clinical outcomes.</p> Results <p>Clathrin-dependent endocytosis mediated by Clathrin Heavy Chain was the primary pathway of cetuximab-bound EGFR internalization. Knockdown of clathrin-independent endocytosis genes or inhibition of macropinocytosis did not affect cetuximab-bound EGFR internalization. Ubiquitin Protein Ligase E3 Component N-Recognin 4 (UBR4) was identified as a critical mediator of EGFR degradation.</p> <p>UBR4 knockdown promoted EGFR recycling, enhanced cell proliferation, and reduced apoptosis in response to cetuximab. High UBR4 expression in CRC tissues correlated with better responses and longer progression-free survival in patients treated with anti-EGFR mAb therapy.</p> Conclusions <p>UBR4 promotes clathrin-dependent EGFR degradation, enhancing anti-EGFR therapeutic efficacy, and may serve as a predictive biomarker in metastatic CRC.</p>

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UBR4 enhances efficacy of anti-EGFR antibody by facilitating clathrin-dependent EGFR endocytosis in colorectal cancer

  • 期刊论文

  • 发表日期：

    2026年1月5日

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  • Akira Fukuya,
  • Yasushi Sato,
  • Yasuyuki Okada,
  • Tamotsu Sagawa,
  • Yutaka Kawano,
  • Masahiro Bando,
  • Koichi Okamoto,
  • Hiroshi Miyamoto,
  • Masahiro Sogabe,
  • Tetsuji Takayama

摘要

Background

Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) effectively treat metastatic colorectal cancer (CRC); however, predicting response to these therapies remains challenging. Here, we aimed to identify key regulators of EGFR internalization as predictive biomarkers for anti-EGFR mAb therapy in CRC.

Methods

CRC cell lines were treated with cetuximab and EGFR internalization was analyzed using siRNA knockdowns, inhibitors, and proteomic analyses. Key proteins mediating cetuximab-bound EGFR internalization were identified through immunoprecipitation and tandem mass spectrometry and validated using RT-PCR, co-immunoprecipitation, immunofluorescence, cell viability, and apoptosis assays. Immunohistochemistry was performed to correlate findings with clinical outcomes.

Results

Clathrin-dependent endocytosis mediated by Clathrin Heavy Chain was the primary pathway of cetuximab-bound EGFR internalization. Knockdown of clathrin-independent endocytosis genes or inhibition of macropinocytosis did not affect cetuximab-bound EGFR internalization. Ubiquitin Protein Ligase E3 Component N-Recognin 4 (UBR4) was identified as a critical mediator of EGFR degradation.

UBR4 knockdown promoted EGFR recycling, enhanced cell proliferation, and reduced apoptosis in response to cetuximab. High UBR4 expression in CRC tissues correlated with better responses and longer progression-free survival in patients treated with anti-EGFR mAb therapy.

Conclusions

UBR4 promotes clathrin-dependent EGFR degradation, enhancing anti-EGFR therapeutic efficacy, and may serve as a predictive biomarker in metastatic CRC.