EGFR is a transmembrane tyrosine kinase receptor that plays a central role in regulating cell division and death. EGFR belongs to the HER family of receptors which comprise four related proteins (EGFR(HER1/ErbB1), ERBB2(HER2), ERBB3(HER3) and ERBB4(HER4)). The HER receptors are known to be activated by binding to different ligands, including EGF, TGFA, heparin-binding EGF-like growth factor, amphiregulin, betacellulin, and epiregulin. After a ligand binds to the extracellular domain of the receptor, the receptor forms functionally active dimers (EGFR-EGFR (homodimer) or EGFR-HER2, EGFR-HER3, EGFR-HER4 (heterodimer)). Dimerization induces the activation of the tyrosine kinase domain, which leads to autophosphorylation of the receptor on multiple tyrosine residues. This leads to recruitment of a range of adaptor proteins (such as SHC, GRB2) and activates a series of intracellular signaling cascades to affect gene transcription, which in turn results in cancer cell proliferation, reduced apoptosis, invasion and metastasis and also stimulates tumor-induced angiogenesis.
The pathways mediating downstream effects of EGFR have been well studied and three major signalling pathways have been identified. The first pathway involves RAS-RAF-MAPK pathway, where phosphorylated EGFR recruits the guanine-nucleotide exchange factor via the GRB2 and Shcadapter proteins, activating RAS and subsequently stimulating RAF and the MAP kinase pathway to affect cell proliferation, tumor invasion, and metastasis. The second pathway involves PI3K/AKT pathway, which activates the major cellular survival and anti-apoptosis signals via activating nuclear transcription factors such as NFKB. The third pathway involves JAK/STAT pathway which is also implicated in activating transcription of genes associated with cell survival. EGFR activation may also lead to phosphorylation of PLCG and subsequent hydrolysis of phosphatidylinositol 4,5 biphosphate (PIP2) into inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), resulting in activation of protein kinase C (PRKC) and CAMK.
Given the prominent importance of EGFR signaling in cancer development, both anti-EGFR monoclonal antibodies and small-molecule EGFR tyrosine kinase inhibitors have been developed. Anti-EGFR antibodies, eg. cetuximab and panitumumab, bind to the extracellular domain of EGFR monomer and compete for receptor binding by the endogenous ligands; in this way they block ligand-induced receptor activation. The small molecule EGFR inhibitors, such as erlotinib, gefitinib and lapatinib, compete with ATP to bind the catalytic domain of the kinase which in turn inhibits EGFR autophosphorylation and downstream signaling. However, these inhibitors are known to be effective in only a small subset of patients. Mutations in the EGFR gene and possible down-stream effectors have been shown to be associated with various clinical outcomes associated with EGFR inhibitor treatments [Articles:17375033, 17285735, 15118073, 15118125].
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
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|Pharmacogenetics and pharmacogenomics: role of mutational analysis in anti-cancer targeted therapy. The pharmacogenomics journal. 2012. Savonarola A, Palmirotta R, Guadagni F, Silvestris F.|