Pharmacological Research 79 (2014) 34–74 Contents lists available at ScienceDirect Pharmacological Research jo urnal homepage: www.elsevier.com/locate/yphrs Invited Review The ErbB/HER family of protein-tyrosine kinases and cancer ∗ Robert Roskoski Jr. Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742, USA a r t i c l e i n f o a b s t r a c t Article history: The human epidermal growth factor receptor (EGFR) family consists of four members that belong to the Received 7 November 2013 ErbB lineage of proteins (ErbB1–4). These receptors consist of a glycosylated extracellular domain, a sin- Accepted 8 November 2013 gle 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 This paper is dedicated to the memory of growth factor and transforming growth factor ␣, none bind to ErbB2, two bind to ErbB3, and seven lig- Dr. John W. Haycock (1949–2012) who ands bind to ErbB4. The ErbB proteins function as homo and heterodimers. The heterodimer consisting of prompted the author to write a review on the treatment of malignant diseases with ErbB2, which lacks a ligand, and ErbB3, which is kinase impaired, is surprisingly the most robust signaling targeted protein kinase inhibitors. 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 Chemical compounds studied in this article: segment. Two ligand-EGFR complexes unite to form a back-to-back dimer in which the ligands are on Afatinib (PubChem CID: 10184653) opposite sides of the aggregate. Following ligand binding, EGFR intracellular kinase domains form an Docetaxel (PubChem CID: 148124) asymmetric homodimer that resembles the heterodimer formed by cyclin and cyclin-dependent kinase. Doxorubicin (PubChem CID: 31703) The carboxyterminal lobe of the activator kinase of the dimer interacts with the amino-terminal lobe 5-Fluorouracil (PubChem CID: 3385) of the receiver kinase thereby leading to its allosteric stimulation. Downstream ErbB signaling mod- Erlotinib (PubChem CID: 176870) ules include the phosphatidylinositol 3-kinase/Akt (PKB) pathway, the Ras/Raf/MEK/ERK1/2 pathway, Gefitinib (PubChem CID: 123631) and the phospholipase C (PLC␥) pathway. Several malignancies are associated with the mutation or Lapatinib (PubChem CID: 208908) increased expression of members of the ErbB family including lung, breast, stomach, colorectal, head Oxaliplatin (PubChem CID: 5310940) Pemetrexed (PubChem CID: 446556) and neck, and pancreatic carcinomas and glioblastoma (a brain tumor). Gefitinib, erlotinib, and afa- Regorafenib (PubChem CID: 11167602) tinib 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 Keywords: ErbB2-overexpressing breast cancer. Trastuzumab, pertuzumab, and ado-trastuzumab emtansine, which Breast cancer are given intravenously, are monoclonal antibodies that target the extracellular domain and are used for Colorectal cancer the treatment of ErbB2-positive breast cancer; ado-trastuzumab emtansine is an antibody-drug con- Monoclonal antibody therapy Non-small cell lung cancer jugate that delivers a cytotoxic drug to cells overexpressing ErbB2. Cetuximab and panitumumab are Small molecule protein kinase inhibitor monoclonal antibodies that target ErbB1 and are used in the treatment of colorectal cancer. Cancers Targeted cancer therapy treated with these targeted drugs eventually become resistant to them. The role of combinations of tar- geted 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. © 2013 Elsevier Ltd. All rights reserved. Contents 1. Introduction . 35 2. Overview of the ErbB/HER protein kinase family and their ligands. 35 2.1. ErbB protein kinases. 35 2.2. ErbB ligands . 36 Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; ado-trastuzumab emtansine, ado-trastuzumab-DM1; AL, activation loop; AR, amphiregulin; BTC, beta- cellulin; C-spine, catalytic spine; CAQ, 4-(3-chloroanilino) quinazoline; CDK, cyclin-dependent kinase; CNS, central nervous system; CRC, colorectal cancer; EC, extracellular; EGFR, epidermal growth factor receptor; EPG, epigen; EPR, epiregulin; FDA, United States Food and Drug Administration; FISH, fluorescent in situ hybridization; HB-EGF, heparin-binding epidermal growth factor-like growth factor; Nrg, neuregulin; JM, juxtamembrane; mAb, monoclonal antibody; LE, ligand efficiency; LipE, lipophilic effi- ciency; NSCLC, non-small cell lung cancer; PI3K, phosphatidylinositol 3-kinase; PK, protein kinase; PLC, phospholipase C; PTEN, phosphatase and tensin homolog; R-spine, regulatory spine; TGF␣, transforming growth factor ␣; TM, transmembrane; VEGFR, vascular endothelial growth factor receptor; MW, molecular weight. ∗ Tel.: +1 828 891 5637; fax: +1 828 890 8130. E-mail address: [email protected] 1043-6618/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.phrs.2013.11.002 R. Roskoski Jr. / Pharmacological Research 79 (2014) 34–74 35 3. ErbB/HER protein-tyrosine kinase structure and function . 38 3.1. The extracellular ligand-binding domains . 38 3.2. Catalytic residues in the amino and carboxyterminal lobes of the active and dormant ErbB1 protein kinase domains . 39 3.3. Structures of the hydrophobic spines in the active and dormant ErbB1 protein kinase domain . 42 3.4. Activation of the ErbB protein kinases . 42 3.4.1. Asymmetric dimer formation . 42 3.4.2. Role of the juxtamembrane segment and transmembrane helices in enzymatic activation . 43 3.4.3. A functional model of EGFR . 45 4. ErbB/HER signaling and receptor down regulation. 45 4.1. ErbB signaling . 45 4.2. ErbB down regulation . 48 4.3. Nuclear localization and function of the ErbB family . 48 5. ErbB/HER family gene amplification, overexpression, mutation, and cancer . 50 5.1. Lung cancer . 50 5.1.1. Classification and general treatment . 50 5.1.2. Mutant ERBB1 oncogenic activation . 50 5.1.3. Targeted inhibition of mutant EGFR by gefitinib, erlotinib, and afatinib . 52 5.1.4. Mutant ERBB2 oncogenic activation and pharmacological inhibition in lung cancer . 55 5.2. Breast cancer . 56 5.2.1. Classification and general treatment . 56 5.2.2. Targeted breast cancer treatments . 56 5.2.3. Activating ERBB2 mutations and breast cancer . 59 5.2.4. BRCA1 and BRCA2 genes and breast cancer. 60 5.3. Gastric cancer. 60 5.4. Colorectal cancer . ..