Trastuzumab emtansine: mechanisms of action and drug resistance

Breast Cancer Research

Table 1 Mechanisms of action of trastuzumab and trastuzumab emtansine

	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]

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.

ISSN: 1465-542X