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Table 1 Mechanisms of action of trastuzumab and trastuzumab emtansine

From: Trastuzumab emtansine: mechanisms of action and drug resistance

  Mechanism of action Mechanism causing trastuzumab resistance
Trastuzumab   
  Fab-mediated Down-regulation of HER2 on the plasma membrane [19] Masking of trastuzumab binding epitope of HER2 [20, 21]
  Inhibition of HER2 ectodomain shedding [22] Expression of p95HER2 [23]
  HLA-I-restricted antigen presentation of HER2 [24] Activation of the IGF-IR pathway [25]
  Inactivation of the PTEN-PI3K/AKT pathway [26] Defects in the PTEN-PI3K/AKT pathway [26]
  Induction of apoptosis [19] Overexpression of cyclin E [27]
  Inhibition of angiogenesis [28] Autocrine production of EGF-related ligands [29]
  Fc-mediated ADCC [30] Impaired ADCC [31]
T-DM1   
  Trastuzumab part   
   Fab-mediated Inhibition of HER2 ectodomain shedding [16]  
  Inhibition of PI3K/AKT signaling pathway [16]  
   Fc-mediated ADCC [16, 18]  
  DM1 part Mitotic arrest [11]  
  Apoptosis [11, 17, 18]  
  Mitotic catastrophe [18]  
  Disruption of intracellular trafficking [18]  
  1. ADCC, antibody-dependent cell-mediated cytotoxicity; AKT, protein kinase B; EGF, epidermal growth factor; HER2, human epidermal growth factor receptor-2; HLA, human leukocyte antigen; IGF-IR, insulin-like growth factor-I receptor; PI3K, phosphatidylinositol 3′-kinase; PTEN, phosphatase and tensin homolog; T-DM1, trastuzumab emtansine.