Cancer Cell

Cancer Cell. and small molecule EGFR tyrosine kinase inhibitors into our current treatment paradigms. Keywords: EGFR, tyrosine kinase, lung cancer, therapy, oncology HER FAMILY/EGFR- BACKGROUND/ROLE IN Cichoric Acid CANCER Cichoric Acid The epidermal growth factor receptor (EGFR) family, a member of the subclass I of the transmembrane receptor tyrosine kinase superfamily, consists of four closely related members: EGFR/ERBB1/HER1, ERBB2/HER2, ERBB3/HER3, and ERBB4/HER4 [1]. The founder member, EGFR was first identified as a 170-kDa protein around the membrane of A431 epidermoid cells and other ERBB members were identified by screening of cDNA libraries for EGFR related molecules [2,3]. These receptors are normally expressed in various tissues of epithelial, mesenchymal, and neural origin. The crucial roles of the EGFR family proteins are supported by a series of knockout mouse studies. Mice lacking EGFR die between day 11.5 of gestation and day 20 after birth, depending on their genetic backgrounds [4]. Analyses of the knockout mice reveal placental defects and lung immaturity, both of which can be the causes of death. They also show abnormalities in the bone, brain, heart, and various epithelial organs such Cichoric Acid as gastrointestinal tract, skin, hair follicles and eyes [4]. Detailed analyses show that deletion of EGFR leads to impaired branching and deficient alveolization and septation in lungs [5]. In addition, type II pneumocytes are immature, and there is a lack of Rabbit Polyclonal to PKR response in up-regulation of surfactant protein C in mice lacking EGFR [5]. Mice lacking ERBB2 , ERBB3, or ERBB4 are embryonic lethal and have defects in cardiac and neuronal development [4]. In mammals, eleven growth factors bind to the ERBB receptors: EGF, transforming growth factor (TGF), heparin-binding EGF-like growth factor, amphiregulin, beta-cellulin, epiregulin, epigen, and neuregulin1-4, of which seven are ligands of EGFR [6,7]. Upon binding, the ERBB receptors form homo- or hetero-dimers, resulting in autophosphorylation of the receptors. Of note, mice lacking EGF show no overt phenotype [8]. Mice lacking TGF show hair follicle, skin, and eye abnormalities, however, they are viable and fertile [9,10]. These observations indicate that there is a high level of redundancy among ligands. Given the pivotal roles of the ERBB receptors in normal development, one can imagine that dysregulation of these genes or proteins can lead to tumorigenesis. Indeed, EGFR is usually overexpressed in a variety of human cancers including lung, head and neck, colon, pancreas, breast, ovary, bladder and kidney, and gliomas [11,12]. More than 60% of non-small cell lung cancers (NSCLCs) show EGFR overexpression, whereas no overexpression is usually detected in small cell lung cancer [13]. The overexpression of EGFR is usually presumably caused by multiple epigenetic mechanisms, gene amplification, and oncogenic viruses [11]. It has been shown that EGFR expression is associated with poor prognosis [14]. In addition to EGFRs themselves, the EGFR ligands may also play an important role in lung tumorigenesis. EGF, TGF, and amphiregulin are expressed in NSCLCs, and activate EGFR and its downstream signaling pathways by autocrine loops [15]. In addition, a distinct ligand for ERBB3 and ERBB4, called neuregulin-1 is usually overexpressed in NSCLC [15]. EGFR MUTATIONS DISCOVERY/BIOCHEMISTRY The EGFR protien consists of three regions: an extracellular ligand-binding region, a single transmembrane helix region, and a cytoplasmic region. The tyrosine kinase domain name accounts for approximately 50% of the cytoplasmic region, with the remainder composed of the 38 amino acid cytoplasmic juxtamembrane (JM) region and the 225 amino acid carboxyl terminal (CT) region [16]. As shown in Figure ?Physique1,1, mutations in the EGFR gene cluster in specific areas, suggesting that these areas are crucial for receptor function or regulation. Open in a separate window Physique 1 Oncogenic EGFR variantsCartoon shows the positions of key EGFR mutations/variants in the corresponding domains. Mutations in.