What is the mechanism of action of trastuzumab?

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Mechanism of Action of Trastuzumab

Trastuzumab is a humanized monoclonal antibody that binds with high affinity to the extracellular domain IV of the HER2 receptor, inhibiting HER2-mediated signal transduction cascades and stimulating antibody-dependent cellular cytotoxicity (ADCC) against tumor cells overexpressing HER2. 1, 2, 3

Primary Molecular Mechanisms

Receptor Binding and Signal Inhibition

  • Trastuzumab binds to domain IV of the HER2 extracellular domain, blocking ligand-independent HER2 signaling and interfering with the signal transduction cascade initiated by HER2 overexpression 1
  • The antibody inhibits HER2-HER4 heterodimerization and blocks downstream signaling pathways including the ras-Raf-MAPK and PI3K/Akt pathways 2, 4
  • This binding does not directly block the HER2-HER2 homodimerization interface but instead induces allosteric conformational changes that affect receptor function 5

Immune-Mediated Cytotoxicity

  • Trastuzumab acts as a mediator of antibody-dependent cellular cytotoxicity (ADCC), preferentially targeting cancer cells that overexpress HER2 compared to cells without HER2 overexpression 2, 3
  • This immune-mediated mechanism contributes significantly to the antitumor activity observed in vivo 4

Cellular Effects on Tumor Cells

Cell Cycle and Proliferation

  • Trastuzumab blocks cell cycle progression by inducing the formation of p27/Cdk2 complexes, leading to growth arrest 4
  • The antibody inhibits proliferation of human tumor cells that overexpress HER2 in both in vitro assays and animal models 3

Receptor Downregulation

  • Trastuzumab induces HER2 receptor downmodulation, reducing the total number of HER2 receptors available on the cell surface 4
  • The antibody inhibits HER2 cleavage, which precedes antibody-induced receptor downmodulation and may contribute to antitumor activity 4

Additional Antitumor Mechanisms

Angiogenesis Inhibition

  • In vivo, trastuzumab inhibits angiogenesis, reducing the tumor's ability to develop new blood vessels necessary for growth and metastasis 4

Synergy with Chemotherapy

  • Cytotoxic agents interact with trastuzumab in a synergistic fashion, enhancing the overall antitumor effect when used in combination 1

Clinical Relevance of Mechanism

HER2 Expression Requirements

  • HER2 overexpression is required for responsiveness to trastuzumab therapy, with patients showing IHC 3+ or FISH-positive results benefiting most from treatment 1
  • Trastuzumab induces responses in approximately 15-25% of selected patients with metastatic cancer as a single agent 2, 6
  • Patients with 3+ HER2 overexpression by IHC or positive FISH results benefit more than those with 2+ expression levels 2, 6

Cardiac Effects Related to Mechanism

  • Trastuzumab inhibits HER2 signaling in cardiomyocytes, blocking an important protective, growth-promoting, and anti-apoptotic pathway in the myocyte 2
  • This mechanism reduces AMP kinase activity and decreases ATP availability to the myocyte, explaining the cardiotoxic effects observed with treatment 2
  • Unlike anthracyclines, trastuzumab does not cause myocyte loss, and the cardiotoxicity is generally reversible (Type II cardiomyopathy) 2

Comparison with Other HER2-Targeted Agents

  • Pertuzumab binds to a different epitope of the HER2 receptor and has complementary mechanisms of action to trastuzumab, providing greater antitumor effect when administered together 2
  • Lapatinib is a small-molecule tyrosine kinase inhibitor of both HER2 and EGFR (HER-1), with a different mechanism than the monoclonal antibody approach 1

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Guideline

Trastuzumab Mechanism of Action and Effects

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2025

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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