Schematic representation of the primary epidermal growth factor receptor (EGFR) signaling pathway. During normal EGFR signaling, receptor activation is dependent on ligand-mediated receptor dimerization. Once the subunits dimerize, a series of phosphorylation events serve to enhance EGFR kinase activity to stimulate the activation of downstream targets. Downstream signals are propagated by EGFR through three central pathways via both the direct phosphorylation of downstream targets (the JAK/STAT pathway) and the membrane recruitment of key adaptor proteins (the PI3K/AKT and MAPK pathways) to promote cell survival and proliferation. The EGFR signaling through a conserved core of three downstream signaling pathways demonstrates how the activation of this pathway via parallel RTKs, such as HER2, HER3, and MET, can circumvent the inhibitory effects of cetuximab and erlotinib on EGFR. EGFR, epidermal growth factor receptor; JAK/STAT, Janus activated kinase/signal transducer and activator of transcription; PI3K/AKT, phosphoinositide 3-kinase/protein kinase B; MAPK, mitogen-activated protein kinase; HER2, human epidermal growth factor receptor 2; HER3, human epidermal growth factor receptor 3; MET, hepatocyte growth factor receptor; SOS, son of sevenless; GRB2, growth factor receptor-bound protein 2; RAS, rat sarcoma family of proteins; RAF, rapidly accelerated fibrosarcoma; MEK, MAPK kinase; PTEN, phosphatase and tensin homolog; mTOR, mammalian target of rapamycin; FOXO, forkhead box proteins; NF-κB, nuclear factor-kappa B.