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RC48 Induces Senescence in HER2-Expressing Colon Cancer Cells by Activating the CDKN1A-RB-E2F1 Pathway.

Jiaxue Wu1, Qianqian Li1, Xiangyu Cheng2

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Current Cancer Drug Targets
|July 17, 2025
PubMed
Summary

RC48, an anti-HER2 antibody-drug conjugate, shows antitumor effects in colon cancer by inducing cellular senescence. This mechanism, mediated by increased CDKN1A expression, is effective in both HER2-high and HER2-low tumors.

Keywords:
ADC drug.CDKN1AHER2RC48cellular senescencecolon cancer

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • RC48 is an anti-HER2 antibody-drug conjugate with demonstrated antitumor activity in colon cancer.
  • The drug exhibits efficacy in tumors with both high and low HER2 expression.
  • Understanding the mechanisms of RC48 in colon cancer is crucial for optimizing its clinical application.

Purpose of the Study:

  • To investigate the underlying antitumor mechanisms of RC48 in colon cancer cells.
  • To explore the role of HER2 expression levels in RC48's efficacy.
  • To identify key molecular pathways involved in RC48's therapeutic effect.

Main Methods:

  • Cell-based assays (transwell, flow cytometry) were used to assess RC48's effects on HT29 (HER2-high) and SW480 (HER2-low) colon cancer cells.
  • Proteomic analysis was employed to identify proteins and pathways affected by RC48 treatment.
  • Senescence was validated using β-Galactosidase staining and ELISAs for senescence-associated secretory phenotype factors.
  • Bioinformatics analysis correlated protein expression with HER2 levels.

Main Results:

  • RC48 inhibited the growth of both HT29 and SW480 colon cancer cells.
  • Proteomic and bioinformatics analyses revealed that RC48 significantly enhanced CDKN1A expression in both cell lines.
  • RC48 treatment promoted cellular senescence, evidenced by increased β-Galactosidase activity and secretion of senescence-associated factors.
  • Overexpression of CDKN1A alone suppressed colon cancer cell growth, suggesting its critical role.

Conclusions:

  • CDKN1A-mediated cellular senescence is identified as a key antitumor mechanism of RC48 in colon cancer, regardless of HER2 expression levels.
  • This finding provides a novel theoretical basis for the clinical application of RC48.
  • Further in vivo and clinical studies are warranted to validate these findings and elucidate the regulatory relationship between CDKN1A and HER2.