Fig. 4: T-DM1 resistance arising from dysfunctional intracellular trafficking and metabolism.
From: Mechanisms of resistance to trastuzumab emtansine (T-DM1) in HER2-positive breast cancer
HER2–T-DM1 complex internalisation might be reduced by enhanced recycling of HER2–T-DM1 complexes back to the plasma membrane, thereby promoting the efflux of T-DM1. Altered expression of certain endocytic and cytoskeletal proteins could impair normal transit of HER2–T-DM1 complexes through the endosomal maturation pathway. Altered lysosomal pH regulation resulting in decreased acidity of lysosomal vesicles can reduce catabolism of HER2–T-DM1 to lysine-MCC-DM1 and prevent the release of the active compound. Reduced expression of lysosomal transporter proteins, such as SLC46A3, might also impair the release of lysine-MCC-DM1 into the cytoplasm.
