Targeting of NSCLC by VEGF inhibitors and EGFR TKIs. Bevacizumab, a monoclonal antibody, recognizes VEGF and prevents it from binding to the VEGFR which disrupts angiogenesis, halting tumor growth and metastasis. Sorafenib disrupts angiogenesis by inhibiting multiple receptors, including VEGFR, PDGFR-β, and RAF-1, as well as Flt3 and c-kit (not shown). Erlotinib and gefitinib reversibly bind to and inhibit the tyrosine kinase domain of the EGFR, cetuximab reversibly binds to the ligand-binding domain of the EGFR, and afatinib and PF00299804 irreversibly bind to and inhibit the tyrosine kinase domain of the EGFR to disrupt tumor proliferation and survival. Akt, protein kinase B; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PDGF-β, platelet-derived growth factor-β; PDGFR, platelet-derived growth factor receptor; PIK3, phosphatidylinositol 3-kinase; Raf-1, v-raf 1 murine leukemia viral oncogene homolog 1; Ras, retrovirus-associated DNA sequences; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.