Dual HER2 inhibition strategies in the management of treatment-refractory metastatic colorectal cancer: History and status

Figure 1 Epidermal growth factor receptor-related signaling pathways and anti-epidermal growth factor receptor and anti-human epidermal growth factor receptor 2 targeted drugs in colorectal cancer. A: Following ligand binding, the epidermal growth factor receptor (EGFR) (HER1) forms active homo- or heterodimers, resulting in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors. This triggers the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways that transmit mitogenic signals to the nucleus; B: Dimerization of the receptors can be inhibited by EGFR-targeted (cetuximab or panitumumab) or HER2-targeted antibodies (trastuzumab or pertuzumab). Small molecule tyrosine kinase inhibitors (neratinib, afatinib, or lapatinib) can block EGFR and HER2 signaling by preventing adenosine triphosphate binding to the catalytic domain of protein kinases.