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When more target antigen expression is less

Charles Dumontet1

  • 1Université Claude Bernard Lyon 1, INSERM U-1052, CNRS 5286, Centre Léon Bérard, Hospices Civils de Lyon, Centre de Recherche en Cancérologie de Lyon, 69008 Lyon, France.

Cancer Cell
|May 28, 2026
PubMed

Insights

Resistance to antibody drug conjugates (ADCs) can arise from low target antigen expression. This study reveals that increased NECTIN4 expression paradoxically reduces NECTIN4-ADC internalization and increases extracellular release in resistant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • Antibody drug conjugates (ADCs) are crucial cancer therapeutics.
  • Resistance to ADCs is a significant clinical challenge.
  • Low target antigen expression is a known mechanism of ADC resistance.

Purpose of the Study:

  • To investigate the role of target antigen expression in ADC resistance.
  • To elucidate the mechanisms underlying resistance to NECTIN4-targeted ADCs.
  • To identify novel strategies for overcoming ADC resistance.

Main Methods:

  • Analysis of NECTIN4 expression in resistant tumor cell subpopulations.
  • Assessment of NECTIN4-ADC internalization and payload delivery.
  • Quantification of extracellular ADC release.

Main Results:

  • Increased NECTIN4 expression was observed in a resistant tumor cell subpopulation.
  • Higher NECTIN4 levels correlated with reduced NECTIN4-ADC internalization.
  • Enhanced extracellular release of NECTIN4-ADCs was detected in resistant cells.

Conclusions:

  • Contrary to expectations, elevated NECTIN4 expression can contribute to ADC resistance.
  • This resistance mechanism involves impaired ADC internalization and increased release.
  • Understanding this phenomenon is critical for optimizing ADC therapy.

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