Table 2 Potential factors that may cause resistance to trastuzumab emtansine

  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