Trastuzumab (anti-HER2 monoclonal antibody) mediates anti-tumour effects through which primary mechanism in HER2-overexpressing breast cancer?

• A Competitively inhibits EGF and heregulin binding to the HER2 extracellular domain only
• B Inhibits intracellular HER2 tyrosine kinase domain directly, preventing autophosphorylation
• C Binds domain IV of HER2 extracellular domain, blocking receptor dimerisation, inducing ADCC, preventing HER2 shedding and cleavage, and causing receptor internalisation/downregulation ✓
• D Activates natural killer cells via Fc-gamma-RIII exclusively, causing antibody-dependent cellular cytotoxicity

Explanation

Trastuzumab binds the juxtamembrane domain IV of HER2's extracellular domain. Its mechanisms include: (1) blocking receptor dimerisation/activation; (2) mediating antibody-dependent cellular cytotoxicity (ADCC) via the Fc region; (3) preventing metalloprotease-mediated shedding of the HER2 extracellular domain (which generates the constitutively active p95-HER2 fragment); and (4) promoting receptor internalisation and downregulation. Pertuzumab, by contrast, binds domain II and blocks HER2–HER3 heterodimerisation; lapatinib inhibits the intracellular kinase domain.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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