Trastuzumab (Herceptin) is used for HER2-positive breast cancer. Beyond blockade of HER2 receptor signaling, which additional mechanism of action contributes to its anti-tumor efficacy?
- A Inhibition of dimerization between HER2 and EGFR (HER1) by a mechanism identical to pertuzumab
- B Induction of HER2 internalization and lysosomal degradation preventing receptor recycling
- C Complement-dependent cytotoxicity (CDC) causing direct membrane lysis of HER2-positive cells
- D Antibody-dependent cellular cytotoxicity (ADCC) mediated by NK cells and macrophages binding the Fc region of trastuzumab bound to HER2-positive tumor cells ✓
Explanation
Trastuzumab works by multiple mechanisms: (1) binding subdomain IV of HER2 extracellular domain, blocking ligand-independent signaling and preventing downstream PI3K/AKT and RAS/MAPK activation; (2) preventing proteolytic shedding of the HER2 extracellular domain; and (3) crucially, its IgG1 Fc region recruits immune effector cells (NK cells, macrophages) via FcgammaRIII (CD16), mediating antibody-dependent cellular cytotoxicity (ADCC) against HER2-overexpressing cells. ADCC is considered a major component of trastuzumab's in vivo anti-tumor efficacy. Pertuzumab (not trastuzumab) specifically blocks the HER2 dimerization arm by binding subdomain II.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.