Figure 4.

Signal transduction pathways drive cancer metastasis. The signaling pathways of HER family members, VEGF and IGF-1R and the current drugs that target these oncoproteins in cancer are shown. HER-2 can heterodimerize with any of the ligand-activated HER receptors (HER-1, HER-3 or HER-4) and this association leads to intracellular signaling via 2 major pathways, the MAPK pathway and the PI3K pathway, leading to proliferation, cell survival, metastasis and angiogenesis. On the other hand, VEGF can bind to its main receptor, VEGFR-2 (KDR), and this binding causes intracellular phosphorylation of the receptor, thereby stimulating the PI3K pathway and stimulating angiogenesis. The signaling pathways can be targeted extracellularly using humanized monoclonal antibodies, such as trastuzumab and pertuzumab (HER-2), cetuximab (EGF receptor), bevacizumab (Avastin) (VEGF), and cixutumumab (IGF-1R) which can prevent ligand binding and activation of the receptors or can directly block binding of an activated receptor to another. At the intracellular level, small-molecule inhibitors, such as sunitinib (VEGF), lapatinib (HER-1 and HER-2) and erlotinib (HER-2), can disrupt the phosphorylation sites and directly prevent activation of the PI3K or MAPK pathways. P: Phosphate; VEGFR: VEGF receptor.