A 52-year-old woman with HER2-positive metastatic breast cancer is started on trastuzumab. The drug's mechanism of action includes:

• A Intracellular blockade of HER2 tyrosine kinase domain by competitive ATP inhibition
• B Downregulation of VEGF expression in HER2-positive tumour cells, reducing angiogenesis
• C Activation of intrinsic apoptosis pathway via p53 stabilisation in HER2-overexpressing cells
• D Binding to subdomain IV of the HER2 extracellular domain, preventing receptor dimerisation, cleavage, and signalling, and recruiting immune effector cells (ADCC) ✓

Explanation

Trastuzumab (Herceptin) is a humanised monoclonal antibody that binds the juxtamembrane subdomain IV of the HER2 (ErbB2) extracellular domain. This prevents: (1) ligand-independent HER2 dimerisation and downstream signalling (PI3K/AKT, MAPK pathways); (2) metalloprotease-mediated HER2 ectodomain cleavage (which generates a constitutively active p95 fragment); and (3) the Fc portion recruits NK cells and macrophages for antibody-dependent cellular cytotoxicity (ADCC). Intracellular tyrosine kinase blockade is the mechanism of lapatinib.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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