Figure 1.

Non–small cell lung cancer HER2 tumorigenesis pathways and targeted therapy mechanisms. The HER2 extracellular domain does not have a known soluble ligand and is activated by forming homo or heterodimers, which leads to phosphorylation and activation of downstream PI3K/AKT and MEK/ERK pathways. (1) Tyrosine kinase inhibitors block phosphorylation of the tyrosine kinase residues, inhibiting cell proliferation. (2) Monoclonal antibodies bind to the extracellular domain of HER2 to block homo and heterodimerization. (3) Antibody–drug conjugates (ADC) incorporate the HER2 targeted actions of trastuzumab with a cytotoxic component (microtubule inhibitor or topoisomerase I inhibitor) connected by a cleavable tetrapeptide-based linker. Upon degradation of the HER2-ADC complex in endosomes/lysosomes, the cytotoxic component is released. This allows for selective delivery into HER2 overexpressing cells, resulting in cell cycle arrest and apoptosis.