A New Target For Anticancer Therapy Biology Essay


Despite major advances in the management of advanced cancer, conventional treatment strategies are rarely curative. In recent years there has been considerable interest in developing new agents to improve the outcome for these patients, focusing in novel therapeutic drugs that specifically target growth factor pathways that are deregulated in tumor cells. Such targeted therapies improve the lack of specificity of traditional cytotoxic agents differentiating between malignant and nonmalignant cells, producing a higher therapeutic index and different toxicity profile than conventional therapies [1]. The characteristics that distinguish cancer cells from noncancerous cells, including lack of differentiation, uncontrolled division, and propensity toward tissue invasion and metastasis, have been well described [2]. Targeting disregulated pathways to stop cancer growth can be less toxic to normal cells, and thus improve tolerability. Anticancer drug discovery has shifted from an empiric random screening approach to a more rational and mechanistic, target-directed approach, where specific abnormalities in cell functioning are modulated in a classical drug receptor fashion [3].

1.Targeted therapies in cancer :

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The goal in the development of targeted therapies is to identify antitumor agents directed against tumor expressed molecules while sparing normal cells. This therapeutic approach leads to increased specificity and efficacy while decreasing the toxicities [4]. A movement towards personalized therapy is occurring in cancer because of increasing evidence that targeted agents can induce responses with only minimal toxicity in patients whose tumors harbor the appropriate aberrant target. For instance, following treatment with growth factor receptor (GFR) inhibitors [5] Cancer cells may acquire the capacity for autonomous and disregulated proliferation through the uncontrolled production of specific molecules that promote cell growth (growth factors) or through abnormal, enhanced expression of specific proteins (growth factor receptors) on the cell membranes to which growth factors selectively bind[6]. Growth factors mediate their diverse biologic responses (control of cellular proliferation, differentiation, migration and metabolism) by binding to and activating cell-surface receptors with intrinsic protein kinase activity [7]. Epidermal growth factor receptor (EGFR) is the first growth factor receptor to be proposed as a target for cancer therapy [8]. Recognition of the epidermal growth factor receptor (EGFR) as an important regulator of tumor cell growth in the early 1980s stimulated the development of a series of molecules specifically designed to inhibit EGFR signaling as anticancer agents [9]. EGF receptor and its ligands are involved in over 70% of all cancers [10]. In normal cells, the expression of EGFR ranges from 40,000 to 100,000 receptors per cell [11]. Overexpression of epidermal growth factor (EGF) ligands and receptors (EGFRs) has been implicated in neoplastic traits of mitogenesis (1), inhibition of apoptosis, cell migration (2), metastases (3), angiogenesis (4, 5), and resistance to standard cytotoxic therapies (6, 7). Experimental evidence suggests that, in principle, EGFR inhibitors can simultaneously suppress many of these properties and induce tumor stasis or regression [12]. The role of receptor tyrosine kinases (RTK) as key regulators of the cellular processes governing proliferation and differentiation has led to intensive efforts focused on identifying selective inhibitors for use in cancer treatments. The epidermal growth factor receptor (EGFR) is the prototypic member of the class I superfamily of receptor tyrosine kinases (RTKs), receptors of this superfamily are expressed in various tissues of epithelial, mesenchymal and neuronal origin and Among the known RTKs egfr are one of the most studied cell signaling families [13]. The epidermal growth factor receptor family consists of 4 transmembrane receptor tyrosine kinases; EGFR, HER2 (erbB-2), HER3 (erbB-3), and HER4 (erbB-4), whose function is to transmit extracellular cues directing proliferation, differentiation, and survival responses [14]. The EGFR tyrosine kinase inhibitors are a group of orally active compounds that have been under investigation for several years [15]. Currently four treatment strategies for targeting EGFR and blocking its downstream signaling pathways have been developed, including

1) Monoclonal antibodies directed against the extracellular domain of EGFR,

2) Small molecules blocking tyrosine-kinase activation intracellularly (tyrosine-kinase inhibitors;


3) Antisense oligonucleotides inhibiting EGFR synthesis and

4) Antibody-based immunoconjugates [16]

i.] Monoclonal Antibodies

Blocking altered biologic pathways with MAbs is one of the most successful therapeutic strategies currently under evaluation in cancer research, and the EGFR is one of the targets against which more MAbs are being developed [17]. There are of different types of monoclonal antibodies as Chimeric monoclonal antibodies, Humanized monoclonal antibodies, Fully human monoclonal antibodies [18].

Table : 1

Monoclonal antibodies targeted to the epidermal growth factor receptor tyrosine kinase [17]

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Site of tumor

Phase of development

Cetuximab(ErbituxTM, IMCC225)










Breast, ovarian, prostate, NSCLC

Phase III


Breast Adjuvant

Marketed Phase III

ii.] Small Molecule TKI

A large number of TKIs are currently being evaluated. They can be classified according to their selectivity (monofunctional agents with EGFR specificity, as opposed to multifunctional agents), and according to the reversibility of their interaction with their target (reversible or irreversible inhibitors) [17].

Table : 2

Small molecules targeted to the epidermal growth factor receptor tyrosine kinase [17]


Site of tumor

Phase of development

Gefitinib (Iressa TM, ZD1839)



Erlotinib (TarcevaTM,OSI-774)

NSCLC, pancreas











Table 3

Percentage of different tumor types expressing EGFR [19]

Tumor type

Tumors with expressed EGFR (%)

Head and Neck




Renal carcinoma








Non-small-cell lung














iii.] Antisense oligonucleotides inhibiting EGFR synthesis

Antisense oligonucleotides are sequence specific for EGFR or EGFR ligand messenger RNAs, decreasing the expression of EGFR and resulting in the inhibition of proliferation and induction of apoptosis. Of all the strategies targeting EGFR, MoAbs and TK inhibitors are currently most often used in patients with CRC or lung cancer (phase II/III trails), whereas EGFR ligand-toxin and immunotoxin conjugates and antisense oligonucleotides are still in the early phases of clinical development (phase I/II trials; Table 1). This article will focus on clinical studies analyzing the effects of MoAbs and TK inhibitors in the treatment of metastatic CRC. [20]

iv.] Antibody-based immunoconjugates

Epidermal growth factor receptor ligand toxin and immunotoxin conjugates are novel drugs that contain an EGFR ligand or an EGFR-binding antibody that is conjugated to a cytotoxic agent. Binding to EGFR triggers ligand-toxin-EGFR internalization, and the toxin thereby induces cell death. [20]

II. EGFR structure, signaling and functioning:

1. Structure:

The EGFR is a 170 kDa membrane-spanning glycoprotein comprising an extracellular ligand-binding domain, a transmembrane domain, and an intracellular cytoplasmic protein domain with tyrosine kinase activity [21]. It also having C-terminal tail that contains specific tyrosine containing sequences that, upon phosphorylation, become binding sites for SH2-containing signaling proteins [22]. Three domains of EGFR can be distinguished the ligand binding extracellular domain, a lipophilic transmembrane domain, and a signal-transducing TK domain located intracellulary [23,24]. The EGFR gene encodes a protein containing 1186 amino acids, 621 residues of which comprise the extra-cellular region [25]. The ligand-binding ectodomain is composed of four subdomains termed L1 (leucine-rich repeats 1), CR1(cysteinerich 1), L2 and CR2 (alternatively I-IV). CR1 contains a b-hairpin loop essential to receptor function [26,27, 28]. Structures of the EGFR ectodomain with EGF or TGF-a demonstrate that binding of ligand to the L1 and L2 domains leads to a conformational change in which the receptor takes on an extended form that exposes this dimerization loop and allows for interaction of receptor ectodomains [29]. In brief, dimerization of EGFR requires the binding of two molecules of monomeric ligand (i.e. EGF) to two molecules of EGFR in a 2 : 2 EGFR:EGFR complex formed from stable 1:1 EGF:EGFR intermediates [30]. The two receptors adopt a 'back-to-back' conformation, with the ligand binding pockets facing outward and interaction mediated by a critical dimerization loop which becomes exposed following intramolecular conformational changes upon ligand binding this ligand binding to the ErbB ectodomain and receptor dimerization induces conformational changes in the intracellular tyrosine kinase domain that leads to receptor autophosphorylation [31, 32].

2. Signaling:

Signal transduction is the communication process used by regulatory molecules to mediate essential cell processes (including growth, differentiation, and survival) in response to stimuli [33]. The signal transduction cascade activated by growth factors receptors, cytokines (IL2, IL3, GM-CSF), and hormones (insulin, Insulin-like growth factor-IGF), involves the 21-kDa guanine-nucleotide-binding proteins encoded by the ras proto-oncogene, of which H-, N-, and K-ras 4A/4B are prototypical [34]. The aberrant activation of Ras proteins is implicated in facilitating virtually all aspects of the malignant phenotype, including cellular proliferation, transformation, invasion and metastasis [35]. There are of different modes of epidermal growth factor receptor signaling are as [36].

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I) Cell-surface and cytoplasmic modes of EGFR signaling.

Kinase-dependent functions.

Kinase-independent functions.

II) Nuclear mode of EGFR signaling.

Detection of nuclear EGFR and EGFRvIII.

Nuclear EGFR and EGFRvIII as transcriptional regulators.

EGFR as a nuclear tyrosine kinase.

Nuclear EGFR as a modulator of DNA repair.

Nuclear EGFR and EGFR-targeted therapy.

Nuclear EGFR and EGFRvIII as indicators for poor clinical outcome.

Trafficking of cell-surface EGFR to the nucleus.

III) Mitochondrial mode of EGFR signaling

Given the functional diversity of proteins that complex with, or are phosphorylated by, the EGFR, it is hardly surprising that EGF stimulation of a cell results in the simultaneous activation of multiple pathways. These pathways are often functionally interlinked and ideally should not be considered in isolation; however, for the sake of simplicity we will discuss them individually and in particular attempt to describe the earliest steps of their EGFR mediated activation [38, 39].

i. Shc, Grb2, and the Ras/MAPK pathway :

The cascade of biochemical events that leads from the EGFR to the activation of the proto-oncogene Ras and, eventually, of the serine/threonine kinase MAPK has been analyzed extensively. The key player in EGF-dependent Ras activation is the adaptor protein Grb2 [40]. Grb2 is constitutively bound to the Ras exchange factor Sos and is normally localized to the cytosol. Following activation of the EGFR kinase and autophosphorylation, the SH2 domain of Grb2 can bind to the EGFR. It must be noted that Grb2 can associate with the receptor either directly (via Y1068 and Y1086 [41]) or indirectly, by binding to EGFR-associated, tyrosine phosphorylated Shc [42]. It has been suggested that association of Shc to EGFR via its PTB domain, leading to its tyrosine phosphorylation and to the recruitment of Grb2, is the main step in EGF-dependent induction of the Ras/MAPK pathway [43].

ii. The Src family of kinases:

c-Src and other members of this family of cytosolic tyrosine kinases have long been implicated in signal transduction from polypeptide growth factor receptors such as the EGFR [44]. Inhibition of Src activity by microinjection of antibodies, by dominant negative Src kinase constructs or by exposure of the cells to Src-specific pharmacological inhibitors, can block EGF-dependent DNA synthesis [45, 46], and reverses the transformed phenotype of EGFR- or ErbB2-overexpressing cells [47]. However, it is still not clear whether Src is a signal transducer downstream of the EGFR or a contributor to EGFR activation [48].

iii. The JAKs and STATs pathways

STATs were first identified as signal transducers downstream of cytokine receptors [49, 50]. In mammals, seven STAT genes have been identified (STAT 1 to 4, 5a, 5b, and STAT6). STAT proteins are inactive transcription factors, which are activated and translocated to the nucleus upon specific receptor stimulation. Classically, STATs are recruited to the intracellular domain of the cytokine receptors through specific binding between STAT SH2 domains and receptor phosphotyrosine residues. Homo- and heterodimerization of STAT proteins is a prerequisite for activation and translocation to the nucleus, and is mediated by tyrosine phosphorylation of critical residues (Y699 in STAT5b, Y694 in STAT5a, and Y701 in STAT1); further residues have also been implicated in the activation of STAT5b [51]. In cytokine signalling, activation is mediated by the JAK family of kinases [52] STAT proteins, in particular STAT-1, 3, and 5, have also been implicated in EGFR signaling [53]. However, as in JAK kinase signalling, activation of STAT transcriptional activity is strictly dependent upon the EGFR tyrosine kinase activity [54]. Phospholipid metabolism: PLD, PLCƳ, and PI3-K EGF stimulation of a cell has marked effects on its phospholipid metabolism, including phosphatidylinositol turnover and production of phosphatidic acid (PA) and arachidonic acid (AA). Of the enzymes involved in these pathways, at least three can be activated directly by the EGFR, i.e., phospholipase C- Ƴ (PLC Ƴ), phosphatidylinositol- 3-kinase (PI3-K), and phospholipase D (PLD), while others, such as phospholipase A2, are regulated indirectly by EGF-mediated activation of other pathways [55]. High expression of EGFR is commonly thought of as the main mechanism by which EGFR signalling is increased in cancer cells. However, a number of alternative mechanisms are likely to be of importance including activating EGFR mutations, decreased levels of phosphatase, increased coexpression of receptor ligands, such as transforming growth factor a (TGFa) and amphiregulin, and heterodimerisation with HER2 and/or the other members of the erbB receptor family, as well as interaction with heterologous receptor systems. Some of these mechanisms have even been found to have an impact on prognosis [56]. Specifically, inhibition of the EGFR signaling pathways has been accomplished extracellularly with specific antibodies to block ligand binding or intracellularly with small molecule inhibitors [57].

III. Mechanism of action :

The EGFR was proprosed as a target for cancer therapy for a variety of reasons including the expression of high levels of EGFR in a variety of tumor types [58]. The antibodies bind to the easily accessible extracelllular domain of the EGFR and compete with ligand binding to the receptor. The low-MW inhibitors, on the other hand, act intracellularly by competing with ATP for binding to the tyrosine kinase portion of the EGFR, thereby abrogating the receptor's enzymatic activity [59,60].

As a result of their effects on the receptor and downstream signaling, anti-EGFR MAbs and the low-MW tyrosine kinase inhibitors (TKIs) interfere with a number of key biological functions regulated by the receptor that satisfactorily explain their antitumor effects. These are summarized below, with antibody studies described first in most cases because they were reported earlier [61].

1. Cell cycle arrest

2. Potentiation of apoptosis

3. Inhibition of angiogenesis

4. Inhibition of tumor cell invasion and metastasis

5. Augmentation of the anti-tumor effects of chemotherapy and radiation therapy [61].

These approaches can be used to target the receptor itself: (1) the design and synthesis of ligand antagonists, (2) the utilization of antibodies, which induce receptor inactivation like Herceptin for Her- 2 and monoclonal antibody 225 against the EGFR and (3) tyrphostins (tyrosine phosphorylation inhibitors, tyrosine kinase inhibitors) which block the kinase activity of the receptors [62]. Monoclonal antibodies might directly affect cancer cell survival by stimulation of an immune response in the patient. Following binding of the Fv region of the immunoglobulin to the cell surface antigen, the Fc, or constant region, may initiate complement mediated Cytotoxicity (CMC) or antibody-dependent cell-mediated Cytotoxicity (ADCC) [63]. Because EGFR-TKIs specifically target the EGFR it might be expected that the level of expression of EGFR would determine tumor sensitivity to these inhibitors. This is a key issue for clinical use of these drugs; specifically, whether only patients with tumors that express or overexpress EGFR should be candidates for treatment [64].

IV. EGFR In Different types of cancers :

Head and neck cancer

Rationale for targeting EGFR in head and neck cancer

SCCHN has proven to be sensitive to inhibition of receptor tyrosine kinases (RTK), specifically EGFR Significantly, elevated EGFR expression detected by immunohistochemistry (IHC) is present in a majority of SCCHN, and is associated with inferior survival, radioresistance, and locoregional failure [65] Early preclinical studies revealed the anti-tumor effects of EGFR-directed monoclonal antibodies in epithelial cancer cell lines [66] and confirmed that EGFR inhibition sensitizes head and neck squamous cancer cells to ionizing radiation [67] Inhibiting EGFR also delays the repair of chemotherapy-induced DNA damage via modulation of the DNA repair genes XRCC1 and ERCC1[68] Recent studies suggest that EGFR translocates to the nucleus where it activates or represses the production of various effector proteins, such as DNA-dependent protein kinase (DNA-PK), an enzyme involved in repair of double-strand breaks of DNA caused by radiation and chemotherapy [69] the central role of EGFR among a network of RTKs, and as master regulator of much cancer-promoting signaling, make this protein an urgent target for therapeutic development.[70]

Breast cancer

Rationale for targeting EGFR in Breast cancer

These receptors play distinct roles in breast malignancies.[71-85] For many years it was believed that EGFR plays a minor role in the development and progression of breast malignancies. However, recent findings have led investigators to revisit these beliefs. Here we will review these findings and propose roles that EGFR may play in breast malignancies. Thus, we will propose the contexts in which EGFR may be a therapeutic target.[86] Epidermal growth factors (EGFs) are important in the biology of both normal and malignant breast tissue, exerting their effects through their tyrosine kinase growth factor receptors.[87] Signalling from these receptor tyrosine kinases is triggered by binding of specific ligands, including EGF, transforming growth factor-α (TGF-α), amphiregulin, epiregulin, betacellulin, heparin-binding EGF-like growth factor (HB-EGF) and neuregulins.[88-91]. Recently, EGFR has once again come to the fore, because of the development of several novel drugs that target EGFR. Because EGFR has not proven to be a useful prognostic/predictive marker of clinical response to EGFR-targeted therapies.[92-97].

Renal cancer

Rationale for targeting EGFR in Renal cancer

Recent studies suggest anticancer therapies targeting the EGFR pathway have shown promising results in clinical trials of RCC patients. Therefore, characterization of the level and localization of EGFR expression in RCC is important for target-dependent therapy. In this study, investigation of the clinical significance of cellular localization of EGFR in human normal renal cortex and RCC.[98] Although prognostic significance of EGFR was confirmed in numerous studies [99,100, 101] the association between EGFR expression and prognosis in clear cell renal cell carcinoma (CCRCC) is still controversial[102-104]. Overexpression of EGFR in renal cell carcinoma (RCC) has been shown in various research, ranging from 40-80%.[105] EGFR Overexpression may be particularly relevant in RCC because it has been shown that EGF and TGF-α can stimulate growth of human renal carcinoma cell lines and antibodies against EGFR can inhibit such growth stimulation.[106] EGFR agents against renal cell carcinoma cells are known to exert their anti-cancer effects via modulating the expression of caspases resulting in induction of apoptosis [107-109] These above observations suggest that targeting these molecular regulators and apoptosis pathways of cancer cell growth and survival might help in achieving a resultant growth inhibition and death of cancerous cells, inhibition of epidermal growth factor receptor extracellular signal regulated protein kinase (EGFR-ERK) activation and induction of apoptosis involving modulation in caspase activation together with a decrease in survivin levels and increase p53 expression in renal cell carcinoma cells.[110]

Cervix/uterus cancer

The mechanism for EGFR overexpression in the majority of cervical squamous cell carcinomas remains to be identified. It is likely that, in the majority of cases, EGFR upregulation happens at the transcriptional level [111] Human papillomavirus (HPV) are considered the major infectious etiologic agents of cervical precancerous lesions and cancers [112] Several studies have shown that HPV E6 and E7 oncoproteins increase the expression and the activation of the EGFR [113] and that E5 protein stimulates recycling of EGFR to the cell surface [114] The E5 gene has been also linked to the expression of EGFR by abrogating degradation of the receptor via inhibition of the endosomal proton-ATPase [115] resulting in an increase in EGFR recycling and overexpression of EGFR. Furthermore, expression of high-risk HPV E6 has been linked to an increase in EGFR levels [116] and changes in functional levels of the HPV E6/E7 proteins may alter the growth rate of cervical carcinoma cell lines by reducing the stability of EGFR at the posttranscriptional level [117]

Esophageal cancers

EGFR expression has been documented in a wide variety of solid tumors including EC [118] The mechanisms underlying the increased expression of EGFR are multifold and include increases in its natural ligands, increased gene transcription and/or amplification, and mutations leading to constitutively active tyrosine kinase activity[119] There are several potential strategies that target EGFR. The monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors (TKIs) of EGFR are the most developed strategies at the present moment. The mAbs bind to the extracellular domain with a higher affinity than the natural ligand and not only interfere with the ligand receptor interaction but also cause internalization and degradation of the receptor [120,121] In contrast, oral TKIs compete with adenosine triphosphate for binding to the receptors tyrosine kinase domain and inhibit the enzymes ability to autophosphorylate and block the receptor-dependent signaling cascade [122]

Pancreatic cancer

EGFR, one of the four ErbB (or HER) receptor tyrosine kinases, is responsible for activation of several membranenuclear pathway, such as (GTPase)-mediated signal transduction to mitogen-activated protein kinase (MAPK) cascade, G protein-coupled receptor (GPCR)-mediated EGFR transactivation via intracellular Ca2+ signaling, phosphatidylinositol polyphosphate (PIP or PI3K/Akt) signaling, etc. mTor acts as a gatekeeper for cellcycle progression from G1 to S phase by mTor-dependent phosphorylation of p70 and 4E-BP1 [123.124.125] In particular, PI3K/Akt signalling has been shown to be involved in many basic cellular functions and there is now strong evidence that the serine/threonine-specific kinase mTor, placed downstream of the PI3K/Akt pathway, is phosphorylated in response to mitogens. In spite of this biological background, EGFR inhibitors have so far shown only modest clinical activity against pancreatic cancer [126,127], thus suggesting that other factors are likely to play a role in this partial failure, including compensatory activation of either downstream pathway effectors or alternative survival pathway [128] In addition, EGFR inhibitor capability to reduce the phenomenon of the paradoxical activation of IGF-I signalling, due to the exposure to mTor inhibitors [129,130] The possibility that a double inhibition of the EGFR pathway could stress antiangiogenic efficacy should also be taken into account.[131,132]

Non small cell lung cancer

MOA is suppression egfr phosphorylation, inhibited MAPK activation and PI3K/Akt pathways, reduced keratinocyte proliferation, and increased p27 kip1 levels and apoptosis [133,134] Also inhibition of cellular functions regulated by the receptor as cell-cycle arrest, potentiation of apoptosis, inhibition of angiogenesis, inhibition of tumor cell invasion and metastasis, and augmentation of the antitumor effects[135].

Prostate cancer

The inhibition of EGFr, and the signal transduction processes that are associated with the receptor, may be a viable method of attacking cancer cells. [136,139] Monoclonal antibodies that target the EGFr and inhibit ligand-induced activation of EGFr have been shown to inhibit tumor growth in vitro and in vivo. [140]

Colon cancer

Ovarian cancer

Glioma cancer

Bladder cancer

Gastric cancer

V. Toxicities related to EGFR inhibitors :