title: The ErbB/HER family of protein-tyrosine kinases and cancer.
abstract: The human epidermal growth factor receptor (EGFR) family consists of four members that belong to the ErbB lineage of proteins (ErbB1-4). These receptors consist of a glycosylated extracellular domain, a single hydrophobic transmembrane segment, and an intracellular portion with a juxtamembrane segment, a protein kinase domain, and a carboxyterminal tail. Seven ligands bind to EGFR including epidermal growth factor and transforming growth factor α, none bind to ErbB2, two bind to ErbB3, and seven ligands bind to ErbB4. The ErbB proteins function as homo and heterodimers. The heterodimer consisting of ErbB2, which lacks a ligand, and ErbB3, which is kinase impaired, is surprisingly the most robust signaling complex of the ErbB family. Growth factor binding to EGFR induces a large conformational change in the extracellular domain, which leads to the exposure of a dimerization arm in domain II of the extracellular segment. Two ligand-EGFR complexes unite to form a back-to-back dimer in which the ligands are on opposite sides of the aggregate. Following ligand binding, EGFR intracellular kinase domains form an asymmetric homodimer that resembles the heterodimer formed by cyclin and cyclin-dependent kinase. The carboxyterminal lobe of the activator kinase of the dimer interacts with the amino-terminal lobe of the receiver kinase thereby leading to its allosteric stimulation. Downstream ErbB signaling modules include the phosphatidylinositol 3-kinase/Akt (PKB) pathway, the Ras/Raf/MEK/ERK1/2 pathway, and the phospholipase C (PLCγ) pathway. Several malignancies are associated with the mutation or increased expression of members of the ErbB family including lung, breast, stomach, colorectal, head and neck, and pancreatic carcinomas and glioblastoma (a brain tumor). Gefitinib, erlotinib, and afatinib are orally effective protein-kinase targeted quinazoline derivatives that are used in the treatment of ERBB1-mutant lung cancer. Lapatinib is an orally effective quinazoline derivative used in the treatment of ErbB2-overexpressing breast cancer. Trastuzumab, pertuzumab, and ado-trastuzumab emtansine, which are given intravenously, are monoclonal antibodies that target the extracellular domain and are used for the treatment of ErbB2-positive breast cancer; ado-trastuzumab emtansine is an antibody-drug conjugate that delivers a cytotoxic drug to cells overexpressing ErbB2. Cetuximab and panitumumab are monoclonal antibodies that target ErbB1 and are used in the treatment of colorectal cancer. Cancers treated with these targeted drugs eventually become resistant to them. The role of combinations of targeted drugs or targeted drugs with cytotoxic therapies is being explored in an effort to prevent or delay drug resistance in the treatment of these malignancies.
authors.affiliation: Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742, USA. Electronic address: rrj@brimr.org.
authors.forename: Robert
authors.initials: R
authors.lastname: Roskoski
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases
keywords: 4-(3-chloroanilino) quinazoline; 5-Fluorouracil (PubChem CID: 3385); ADCC; AL; AR; Afatinib (PubChem CID: 10184653); BTC; Breast cancer; C-spine; CAQ; CDK; CNS; CRC; Colorectal cancer; Docetaxel (PubChem CID: 148124); Doxorubicin (PubChem CID: 31703); EC; EGFR; EPG; EPR; Erlotinib (PubChem CID: 176870); FDA; FISH; Gefitinib (PubChem CID: 123631); HB-EGF; JM; LE; Lapatinib (PubChem CID: 208908); LipE; MW; Monoclonal antibody therapy; NSCLC; Non-small cell lung cancer; Nrg; Oxaliplatin (PubChem CID: 5310940); PI3K; PK; PLC; PTEN; Pemetrexed (PubChem CID: 446556); R-spine; Regorafenib (PubChem CID: 11167602); Small molecule protein kinase inhibitor; TGFα; TM; Targeted cancer therapy; United States Food and Drug Administration; VEGFR; activation loop; ado-trastuzumab emtansine; ado-trastuzumab-DM1; amphiregulin; antibody-dependent cellular cytotoxicity; betacellulin; catalytic spine; central nervous system; colorectal cancer; cyclin-dependent kinase; epidermal growth factor receptor; epigen; epiregulin; extracellular; fluorescent in situ hybridization; heparin-binding epidermal growth factor-like growth factor; juxtamembrane; ligand efficiency; lipophilic efficiency; mAb; molecular weight; monoclonal antibody; neuregulin; non-small cell lung cancer; phosphatase and tensin homolog; phosphatidylinositol 3-kinase; phospholipase C; protein kinase; regulatory spine; transforming growth factor α; transmembrane; vascular endothelial growth factor receptor