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Resistance to antibody-drug conjugates in breast cancer: mechanisms and solutions

Yu-Fei Chen1,2, Ying-Ying Xu3, Zhi-Ming Shao1,2

  • 1Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.

Cancer Communications (London, England)
|November 10, 2022
PubMed

Insights

Antibody-drug conjugates (ADCs) show promise in breast cancer treatment but can face resistance. Understanding resistance mechanisms like impaired drug trafficking and payload issues is key to developing new strategies.

Area of Science:

  • Oncology
  • Pharmacology
  • Biotechnology

Background:

  • Antibody-drug conjugates (ADCs) represent a significant advancement in cancer therapy, particularly for breast cancer.
  • Several ADCs are approved for specific breast cancer subtypes, with many more in clinical development.
  • Clinical observations highlight the emergence of drug resistance, notably with trastuzumab emtansine.

Purpose of the Study:

  • To summarize the known mechanisms of resistance to antibody-drug conjugates (ADCs) in cancer treatment.
  • To discuss strategies for overcoming or preventing ADC resistance.
  • To emphasize the role of predictive biomarkers in optimizing ADC therapy.

Main Methods:

  • Literature review and synthesis of existing research on ADC resistance.
  • Categorization of resistance mechanisms into four main types.
  • Analysis of current and future therapeutic strategies.

Main Results:

  • ADC resistance can stem from antibody-related issues, problems with drug transport within cells, lysosomal dysfunction, or factors related to the drug payload.
  • Trastuzumab emtansine resistance is a notable clinical challenge.
  • Multiple mechanisms contribute to the development of resistance to these targeted therapies.

Conclusions:

  • Understanding the multifaceted mechanisms of ADC resistance is crucial for improving treatment efficacy.
  • Developing novel ADC designs and exploring combination therapies are essential to combat resistance.
  • The identification and application of predictive biomarkers may enhance patient selection and therapeutic outcomes, thereby preventing resistance.
Keywords:
Antibody-drug conjugatebreast cancercombination therapydrug resistancepredictive biomarker

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