Introduction
Trastuzumab emtansine, a HER2-targeted antibody-drug conjugate
Mechanisms of action of T-DM1
Mechanism of action | Mechanism causing trastuzumab resistance | |
---|---|---|
Trastuzumab
| ||
Fab-mediated | Down-regulation of HER2 on the plasma membrane [19] | |
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 | ||
DM1 part | Mitotic arrest [11] | |
Mitotic catastrophe [18] | ||
Disruption of intracellular trafficking [18] |
Trastuzumab-mediated effects
DM1-mediated effects
Activity of T-DM1 in preclinical models and clinical trials
Resistance to T-DM1
T-DM1 resistance in preclinical models
Primary and acquired resistance to T-DM1 in clinical trials
Potential factors that cause resistance to T-DM1
Factors decreasing intracellular DM1 level | |
---|---|
T-DM1 binding to HER2 | Low cancer HER2 expression |
HER2 down-regulation | |
Shedding of HER2 ectodomain | |
Masking of the trastuzumab binding epitope on HER2 p95HER2 expression | |
Intracellular trafficking and lysosomal degradation | Poor HER2-T-DM1complex internalization |
HER2-T-DM1 recycling to plasma membrane | |
Failure of HER2 intracellular trafficking | |
Inefficient lysosomal degradation of T-DM1 | |
Drug efflux | MDR1 expression |
Other factors
| |
Altered DM1 target | Beta1-tubulin mutation |
Autocrine or stromal growth factors | Overexpression of a beta3-tubulin isoform |
Modulators of the apoptotic pathway | Microtubule-associated proteins |
Activation of cell survival pathways |