Medical indication

HER2

HER2 is capable of forming heterodimers with other members of the HER family such as HER1, HER3 and HER4 or it can form a homodimer by interacting with another HER2 protein. The probability of HER2 dimerisation increases with the amplified amounts of HER2 protein present on tumour cells.

Upon dimerisation, the HER2 protein becomes autophosphorylated at the hydroxyl groups of the tyrosine residues located in its cytoplasmic C-terminal domain (Gullick, 2001). The phosphorylation of the HER2 protein triggers a variety of intracellular signalling cascades such as the PI3K/AKT, Ras/MEK/ERK, PLCγ/PKC, and JAK/STAT pathways which ultimately lead to cell proliferation and neoplasia (Appert-Collin et al., 2015, Hsu and Hung, 2016).

Kadcyla mechanism of action

In vivo, the antibody moiety of trastuzumab emtansine selectively binds to domain IV of the HER2 protein on the surface of HER2+ breast cancer cells. The ADC-receptor complex is internalised via clathrin-dependent endocytosis. The cell breaks the complex down within the lysosome via enzymatic digestion, releasing the active metabolite, lysine-MCC-DM1. This active metabolite is released into the cytoplasm and because of its charge at physiological pH, it does not cross the cell membrane minimising the bystander killing effect. The active metabolite lysine-MCC-DM1 inhibits tubulin polymerisation leading to cell cycle arrest and ultimately apoptotic cell death (Joubert et al., 2020).