A patient with HER2-positive breast cancer is treated with trastuzumab emtansine (T-DM1). The mechanism of tumor selectivity of T-DM1 compared to free DM1 (maytansine derivative) is that:

• A Trastuzumab delivers DM1 extracellularly at the tumor cell surface where its local concentration exceeds the therapeutic threshold
• B T-DM1 binds HER2 on tumor cells, undergoes receptor-mediated endocytosis, and releases DM1 intralysosomally via proteolytic cleavage; DM1 then disrupts microtubule polymerization only within HER2+ cells ✓
• C T-DM1 has modified DM1 that is activated only by HER2 receptor tyrosine kinase phosphorylation
• D Trastuzumab prevents DM1 degradation by plasma esterases until it reaches the tumor's acidic microenvironment

Explanation

T-DM1 is an antibody-drug conjugate (ADC) where trastuzumab is linked to DM1 (a potent antitubulin agent) via a non-cleavable thioether linker (MCC). After binding to HER2 on tumor cells, the T-DM1 complex undergoes receptor-mediated endocytosis into lysosomes, where proteolytic degradation of the trastuzumab backbone releases lysine-MCC-DM1 catabolites. DM1 then binds beta-tubulin, inhibiting microtubule polymerization and causing cell death. This targeted delivery exploits HER2 overexpression to concentrate cytotoxic DM1 within tumor cells while minimizing systemic toxicity from free DM1, which would be extremely toxic if given alone.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.