Editorial [ The Role of Epidermal Growth Factor Receptor (EGFR) Targeting Drugs in the Treatment of Cancer Guest Editor: Fortunato Ciardiello ]

Growth factors are locally secreted peptide hormones that are involved in regulating cell proliferation, differentiation and survival by binding to and by activating specific cell membrane receptors on target cells. The epidermal growth factor (EGF) is the first discovered growth factor within a family of related proteins (EGF-like growth factors), which includes transforming growth factor ?? (TGF??), amphiregulin, heparin binding-EGF (HB-EGF), epiregulin, heregulins, neuregulins, and betacellulin [1-3]. EGF-like growth factors bind to and activate one or more receptors of the ErbB family which is composed of four members: the EGF receptor (EGFR) (also known as ErbB1/HER1), ErbB-2 (Neu/HER2), ErbB-3 (HER3) and ErbB-4 (HER4) [1-3]. The EGFR is a 170 kDa transmembrane glycoprotein with an extracellular domain, a hydrophobic transmembrane domain, and an intracellular region containing the tyrosine kinase domain. EGF, TGF?? and amphiregulin are the specific ligands for the EGFR and are commonly produced by the majority of human epithelial cancers. The EGFR exists on the cell membrane as inactive monomers, which dimerize following ligand activation. Depending on the ligand and on the presence of other receptors of the ErbB family, EGFR-EGFR homo-dimers or hetero-dimers between the EGFR and another member of the EGFR family may be formed. In any case, following ligand binding, the tyrosine kinase intracellular domain of the receptor is activated, with autophosphorylation of the intracellular domain, which initiates an intracellular signalling cascade [1-3]. In this respect, EGFR activation is critical for cell proliferation, but also contributes to angiogenesis, invasion, metastasis and inhibition of apoptosis [2]. Activation of the TGF??-EGFR autocrine growth pathway is a common mechanism for autonomous, dysregulated cancer cell growth in the majority of human epithelial cancers. Several mechanisms have been described which are responsible for an uncontrolled activation of this autocrine growth pathway, such as receptor overexpression, increased ligand concentration, decreased receptor turnover, or the presence of aberrant receptor proteins. In this respect, different somatic activating EGFR gene alterations, including small in-frame deletions, point mutations, gene amplification or increased gene copy numbers, and large gene deletions, such as the type-III variant (EGFRvIII), which lacks a portion of the extracellular domain with constitutive, ligand-independent EGFR activation, have been reported in human cancers [1-3]. Overexpression of EGFR and/or TGF?? has been generally associated with advanced disease and poor prognosis and with the development of resistance to chemotherapy, radiotherapy and/or hormonotherapy [4-6]. The results of a large body of preclinical studies and clinical trials suggest that targeting the EGFR could provide a contribution to cancer therapy. Among several potential strategies for targeting EGFR-driven signals, two have reached a therapeutic success in human cancer therapy: the use of EGFR blocking monoclonal antibodies (MAbs) and of small molecules EGFR tyrosine kinase inhibitors (TKIs). MAbs are genrally raised against the EGFR extracellular domain to block ligand binding and receptor activation. TKIs prevent EGFR autophosphorylation and activation since they are direct inhibitors of ATP for binding to the intracellular EGFR tyrosine kinase catalytic domain. Although both types of agents are directed against the same target, they are structurally and functionally different molecules with different pharmacologic characteristics which could be responsible of different therapeutic activities (Table 1). In this respect, MAbs are generally directed against the extracellular domain of the EGFR and are highly specific and selective since they bind exclusively to the EGFR. These immunoglobulins need to be administered intravenously. Following binding to the receptor, MAbs induce intracellular EGFR internalization with subsequent EGFR down-regulation on the cancer cell membrane. In addition, anti-EGFR MAbs can elicit potentially therapeutic immnue functions in the host, such as antibody-dependent cellular cytotoxicity (ADCC), an antitumor mechanism which could be relevant in vivo, as it has been shown for other closely related mAbs, such as the anti-erbB2 mAb trastuzumab [7]. The currently available anti-EGFR MAbs are second generation MAbs. In fact, the first mouse-derived anti-EGFR MAbs had some important therapeutic limitations due to the induction of a human anti-mouse immune response in the majority of patients with the production of human neutralizing anti-mouse immunoglobulins, which were responsible of a consequent rapid clearance of the murine MAb, with limited tumour targeting and therapeutic activity. To overcome this problem, strategies aimed to decrease the immunogenicity of the antibodies have been developed. In this respect, chimeric and humanized MAbs have been engineered by replacing the mouse constant immunoglobulin domains with the corresponding human constant domains [8]. A further improvement has been obtained with the generation of fully human anti-EGFR MAbs [8,9]. On the other hand, anti-EGFR TKIs are low molecular weight compounds which could be administered orally with a daily continous dosing. These molecules possess a different range of specificity against the EGFR. In fact, some anti-EGFR small molecule TKIs are relatively selective for the EGFR, whereas other drugs are also able to efficiently inhibit the tyrosine kinase activity of other members of the erbB/HER family or of other cell membrane tyrosine kinase receptors belonging to other families such as the vascular endothelial growth factor receptor (VEGFR) family. Moreover, anti-EGFR TKIs could differ also for their reversible or irreversible inhibition of the tyrosine kinase activity [10-12]. Recently, a series of somatic in-frame small deletions or pointmutations in specific exons of the EGFR gene which correspond to the ATP binding site pocket in the EGFR protein have been described in a subset of non-small cell lung cancer patients as conferring an increased sensitivity to the antitumor activity of some anti-EGFR TKIs, such as gefitinib and erlotinib [13-15]. However, the presence of these mutant EGFRs does not change the sensitivity to anti-EGFR blocking MAbs, which are able to inhibit cancer cells proliferation independently from receptor mutations [16]. The aim of the present hot topic issue of Current Cancer Therapy Reviews is to provide to the reader a series of review articles which summarize the currently available preclinical and clinical data and the relevant open clinical issues for the optimal use of anti-EGFR directed therapeutic approaches in cancer treatment. A series of clinically relevant problems in this field have been selected and will be discussed, including: 1, the current clinical results on the use of anti-EGFR drugs in nonsmall cell lung cancer (NSCLC) and in colorectal cancer (CRC): 2, the clinical development of anti-EGFR TKIs which could inhibit other relevant growth factor receptor targets such as the VEGFRs; 3, the combination of anti-EGFR agents and radiation therapy in the treatment of head and neck squamous cell carcinoma (HNSCC); 4, the identification of clinical and molecular characteristics which could help to better select cancer patients that are candidate to treatment with EGFR targeted drugs; 5, the clinically relevant problem of intrinsic and acquired resistance to treatment with anti-EGFR agents: 6, the possibility of combining anti-EGFR drugs with other agents which target other molecular pathways which are relevant for cancer development and progression; 6, the methodology issues that the clinical development of molecularly targeted agents such as anti-EGFR drugs have opened for a correct design of clinical trials which could be useful in defining the activity and the efficacy of these drugs in the treatment of human cancers. 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