Trastuzumab (Herceptin) targets HER2 (ErbB2) overexpressed in ~15–20% of breast cancers. Beyond blocking ligand-independent dimerisation, trastuzumab's additional anti-tumour mechanisms include:
- A Direct inhibition of HER2 kinase domain ATP binding, similar to small molecule TKIs like lapatinib
- B Activates complement-dependent cytotoxicity (CDC) as its primary anti-tumour mechanism on HER2+ cells
- C Induction of HER2 receptor downregulation via endocytosis and lysosomal degradation; ADCC (antibody-dependent cellular cytotoxicity) mediated by NK cells via Fc receptor engagement; and inhibition of AKT/mTOR pathway downstream of HER2 ✓
- D Trastuzumab crosses the blood-brain barrier to treat HER2+ brain metastases at standard doses
Explanation
Trastuzumab is an IgG1 monoclonal antibody that binds domain IV of the HER2 extracellular domain. Its mechanisms include: (1) blocking HER2 dimerisation and downstream PI3K/AKT signalling; (2) inducing receptor endocytosis and lysosomal degradation, reducing surface HER2; (3) ADCC — the IgG1 Fc region recruits NK cells and macrophages via FcγRIII receptors; and (4) preventing HER2 ectodomain shedding that generates the constitutively active p95-HER2 fragment. Trastuzumab does NOT directly inhibit kinase activity (that is lapatinib's mechanism) and has poor CNS penetration (trastuzumab-emtansine/T-DM1 and trastuzumab-deruxtecan have better CNS activity).
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.