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The Epidermal Growth Factor Receptor: From Mutant Oncogene in Nonhuman Cancers to Therapeutic Target in Human Neoplasia

From the Departments of Medicine and Cancer Biology and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN.

Address correspondence to Carlos L. Arteaga, MD, Division of Hematology-Oncology, Vanderbilt University, 777 Preston Research Bldg, Nashville, TN 37232-6307; email: carlos.arteaga@ mcmail.vanderbilt.edu.

	ABSTRACT

TOP ABSTRACT STRUCTURE/FUNCTION AND SIGNAL... REFERENCES

 
ABSTRACT: Approximately two decades ago, the epidermal growth factor receptor (EGFR) was discovered to be the proto-oncogene of the mutant, constitutively active oncogenic v-erbB tyrosine kinase, which induces avian erythroblastosis. Unlike the mutant oncogene, the EGFR requires activation by binding of ligand to its extracellular (EC) domain, whereas its cellular effects depend on activation of its cytoplasmic tyrosine kinase. The overexpression of EGFR and its ligands in several human carcinomas and their association with accelerated tumor progression provided a rationale for targeting this network with tumor-selective strategies. Two of those antireceptor approaches, both solidly based on the known structure and function of the EGFR, are discussed. The first strategy involves the development of humanized monoclonal antibodies against the nonconserved receptor’s EC domain. These antibodies block ligand binding and can induce receptor endocytosis and downregulation. The second approach is the generation of ATP mimetics that compete with ATP for binding to the receptor’s kinase pocket, thus disabling signal transduction. Preclinical and early clinical studies already suggest that both of these approaches, either alone or in combination with standard anticancer therapies, will be able to alter the natural history of EGFR-expressing cancers with little to no toxicity to the tumor-bearing host.

	STRUCTURE/FUNCTION AND SIGNAL TRANSDUCTION

TOP ABSTRACT STRUCTURE/FUNCTION AND SIGNAL... REFERENCES

 
THE EPIDERMAL growth factor receptor (EGFR; also known as HER1 or erbB1) is a ubiquitous 170-kd membrane-spanning glycoprotein composed of an amino-terminal extracellular (EC) ligand-binding domain, a hydrophobic transmembrane region, and a cytoplasmic domain that contains the tyrosine kinase domain and a carboxy-terminal region that contains critical tyrosine residues and receptor regulatory motifs.¹ Binding of a specific set of ligands (EGF, transforming growth factor alpha [TGF], amphiregulin, heparin-binding EGF, betacellulin, or epiregulin) to the EC domain activates the cytoplasmic catalytic function by promoting EGFR dimerization and receptor’s autophosphorylation on tyrosine residues.^1,2 These phosphorylated tyrosines serve as the docking sites for a number of signal transducers and adaptor molecules that initiate a plethora of signaling pathways, resulting in cell proliferation, differentiation, migration, adhesion, protection from apoptosis, and transformation, among others. Cytoplasmic signal transducers/pathways that are activated by active EGFR include PLC-gamma-1, Ras-Raf-MEK-MAPKs, phosphatidylinositol-3 kinase (PI3K) and Akt, Src, the stress-activated protein kinases (SAPKs), PAK-JNKK-JNK, and the signal transducers and activators of transcription (STATs)^2,3 (and references therein). However, the specificity and potency of the signaling output from activated EGFR is highly dependent on the identity of the activating ligand as well as the cellular levels of the coreceptors HER2/neu (erbB2), HER3 (erbB3), and HER4 (erbB4), all of which can oligomerize with the EGFR.^2,4 The sites that are autophosphorylated in the C-terminal portion of the EGFR as well as the signaling molecules that associate with the receptor are determined by the heterodimeric partner of the EGFR.

The four members of this HER (erbB) network share an overall structure of two cysteine-rich regions in the EC domain and a cytoplasmic kinase pocket followed by a carboxy-terminal tail with tyrosine autophosphorylation sites. However, HER3 lacks intrinsic kinase activity and no direct ligand thus far has been identified for HER2 (Fig 1). In cells that coexpress HER2, ligand-activated EGFR preferentially recruit HER2 into a heterodimeric complex that exhibits an increased rate of recycling, stability, and signaling potency compared with EGFR homodimers.^5,6 The duration and potency of activation of PI3K, a critical signal for activation of antiapoptosis pathways, are enhanced by coupling of the EGFR to HER3 or HER4, which can couple with PI3K directly, whereas the EGFR and HER2 cannot.^7,8 Of all HER receptors, the EGFR is the only one that can interact directly with c-Cbl, a ubiquitin ligase that targets EGFR to lysosomal degradation after ligand-induced receptor internalization.⁹ Conversely, all other HER receptors are impaired in their intrinsic ability to endocytose and can recycle efficiently to the cell surface.¹⁰ The identity and levels of co-expressed HER receptors in cells can modulate the magnitude of the response to exogenous ligands. The potency of these HER receptor combinations has been studied in HER-null hematopoietic cells transfected with vectors incoding HER1, HER2, HER3, and HER4, either singly or in combination. The proliferation index in the transfected cells has been measured and used as a surrogate marker of the signaling potency by the HER network.⁸ In this system, EGF-induced EGFR/HER2 heterodimers were mitogenically more active than EGFR homodimers. Although EGF-stimulated EGFR homodimers and EGRF/HER3 heterodimers were equally mitogenic, heregulin-induced EGFR/HER3 heterodimers were more potent (Fig 2). Therefore, the ability of ligand-activated EGFR to dimerize with other members of the HER network provides for several possible combinatorial receptor interactions that modulate the quality and potency of signal transduction.

View larger version (20K): [in this window] [in a new window]   Fig 1. Ligand-binding specificity of the EGFR (HER, erbB) family. Diagram depicts the four members of the EGFR family of transmembrane tyrosine kinases: EGFR (HER1), HER2, HER3, and HER4. Numbers denote the degree of homology relative to EGFR. Except for the kinase-deficient HER3, there is high homology in the tyrosine kinase domain. The EC ligand-binding domain, the target of several anti-EGFR antibodies, is less conserved. The C-terminal portion also is less conserved, consistent with the different abilities of these receptors to recruit signal-transducing or adaptor molecules.

View larger version (14K): [in this window] [in a new window]   Fig 2. Proliferative potential of EGFR (HER1) and other HER receptors. HER1, 2, and 3 are represented as transmembrane proteins. Binding of EGF (E) or heregulin (H) results in different homo- and heterodimeric complexes, each with a different proliferation index (below). x indicates the impaired tyrosine kinase activity of HER3. mAb is a monoclonal antibody that binds and induces HER2 homodimers (with modifications from8).

Transfection of high levels of EGFR and its ligand TGF has been shown to induce transformation in vitro.² These studies have suggested that overexpression of the wild-type receptor leads to transformation only in the presence of a ligand. Overexpression of the EGFR ligand TGF in mouse mammary epithelium under the control of mouse mammary tumor virus (MMTV)/long terminal repeat (LTR) tissue-specific promoter results in epithelial hyperplasias and mammary carcinomas.^18,19 Interestingly, studies with fibroblasts²⁰ and transgenic mice²¹ have shown that the transformation induced by excessive EGFR signaling can be accelerated by co-overexpression of neu, the mouse homolog of the HER2 receptor. Fifty percent of bitransgenic mice that express MMTV/TGF and MMTV/neu in mammary epithelium develop metastatic breast tumors within 6 months.²¹ This relatively short latency suggests (1) that activation of the EGFR network may induce cancers in the absence of a large number of additional genetic alterations and (2) that aberrant signaling by the HER (erbB) network might be an early event in the stochastic transformation of breast epithelial cells.

Finally, several human cancers, including cancers of the upper aerodigestive tract, colon, pancreas, breast, ovary, bladder, kidney, and gliomas, display EGFR RNA and/or protein overexpression. This occurs with or without EGFR gene amplification and often is associated with increased expression of TGF or amphiregulin.^22-31 In some of these studies, EGFR-positive tumors that coexpressed receptor ligands exhibited higher proliferation and tumor grade and a worse survival than EGFR-expressing tumors without coexpression of receptor ligands.^26-29 In other reports, cancers of the breast, oral cavity, and lung that co-overexpressed EGFR and HER2/neu fared worse than EGFR-positive cancers that did not express high levels of HER2.^32-34 In breast tumors, EGFR and HER2 co-overexpression was associated with resistance to endocrine therapies.³⁴ Prostate tumors that became androgen-independent acquired colocalization of TGF with EGFR in their tumor compartment,³⁵ suggesting upregulation of autocrine signaling upon tumor progression. Albeit circumstantial, these and other studies^36-39 strongly implicate the EGFR and its network of ligands and HER coreceptors with tumors of a more virulent behavior and hence a worse outcome.

EGFR gene amplification is detected in 40% of human gliomas, where a significant proportion exhibit EGFR gene rearrangements.⁴⁰ The most common mutation involves deletion of exons 2 to 7 and loss of residues 6 to 276 in the EC domain yielding a constitutively active EGFR that is not downregulated by endocytosis.⁴¹ This mutant vIII EGFR also has been reported in medulloblastomas and in breast, ovarian, and non–small-cell lung cancers,⁴² but its contribution to tumor progression in these syndromes is less clear than in high-grade gliomas.

RATIONALE FOR THERAPEUTICALLY TARGETING THE EGFR NETWORK
The coexpression of EGFR and ligands at tumor sites allows for EGFR activation via autocrine/paracrine mechanisms. In support of the operational nature of these signaling pathways in EGFR-expressing tumor cells, interruption of signaling with various EGFR inhibitors has been shown to inhibit tumor cell proliferation and/or viability both in vitro and in vivo⁴³ (and references therein). These observations, coupled with (1) the ability to identify EGFR-expressing human tumors in diagnostic tissue from patients, (2) the association of EGFR overexpression with poor patient prognosis, and (3) the lack of an obvious physiologic role of the EGFR in the adult, all have suggested this network as a rational target for molecular therapeutic strategies.

Studies in mice with homozygous loss of EGFR or its ligands have suggested blocking the receptor itself as a more effective approach to disabling the EGFR network. Genetic inactivation of the EGFR in mice results in a severe failure of epithelial development that sometimes leads to embryonic lethality.^11-13 Conversely, mice with homozygous deletion of TGF are viable with a phenotype limited to their skin and eye.⁴⁴ In addition, mice with germline inactivation of the EGFR ligand amphiregulin are normal except for a severe impairment in mammary gland development.⁴⁵ These data suggest (1) that EGFR ligands have distinct roles and tissue specificity and (2) that the presence of multiple EGFR ligands (Fig 1) may be able to compensate for the deficiencies of some of them. These data also suggest that inhibition of EGFR ligands in cancers may have a limited antitumor effect if ligand compensation occurs. Finally, mutations in the kinase domain in the EGFR severely alter the ability of the receptor to signal in response to any ligand.⁴⁶ These results provide a scientific rationale for treatment approaches that target either the kinase domain or the EC domain to inhibit binding of all potential receptor ligands.

MOLECULAR APPROACHES TO BLOCKING EGFR FUNCTION: ANTIRECEPTOR ANTIBODIES
One antireceptor strategy has been the use of monoclonal antibodies that recognize the receptor’s ectodomain, compete for ligand binding, and induce EGFR dimerization and downregulation from the cell surface (Fig 3).^47,48 In EGFR-dependent tumor cells, this approach has been shown to inhibit EGFR signaling, which leads to cell cycle arrest and/or cell death.^49-52 In addition to blockade of autocrine EGFR signaling, it has been proposed that EGFR antibodies may recruit Fc receptor–expressing immune effector cells, which leads to antibody-dependent cell-mediated cytotoxicity (ADCC) and tumor eradication.^53-55 In one study, less complete inhibition of A431 tumor growth was observed with 225 F(ab')₂ compared with the bivalent 225 monoclonal antibody (mAb),⁴⁷ suggesting that, in addition to kinase blockade, immune mechanisms may contribute to the antitumor activity of intact 225 mAb. A phase I trial with the EGFR mouse mAb 225 revealed selective antibody localization in squamous cancers of the lung that had not been prescreened for EGFR levels.⁵⁶ This important study suggested that the differential expression of EGFR in tumor versus nontumor tissues can provide for a therapeutic window that could be exploited in cancer syndromes with high prevalence of receptor overexpression. In this study, all patients produced human anti-mouse antibodies, which prevented further administration of the EGFR mouse mAb.⁵⁶ A chimeric humanized version of 225 mAb (C225) was generated to avoid the host’s immune response and thus allow for continuous drug delivery that may be required for sustained antitumor action. Interestingly, C225 bound to the EGFR with a higher affinity and exhibited a better antitumor profile against EGFR-overexpressing xenografts than 225 mAb.⁵²

View larger version (19K): [in this window] [in a new window]   Fig 3. Mechanisms of action of EGFR inhibitors. Antibodies prevent ligand access to the EGFR and induce receptor endocytosis. This may result in targeting the receptor to a lysosomal compartment. Small-molecule receptor tyrosine kinase (RTK) inhibitors diffuse into the cell and compete with ATP for binding to the EGFR kinase domain. In turn, both antibodies and small molecules disable EGFR function and block signal transduction downstream the receptor.

SMALL MOLECULAR WEIGHT TYROSINE KINASE INHIBITORS
Another antireceptor approach was based on the observation that mutations in the ATP-binding pocket of the EGFR severely affect the receptor’s tyrosine kinase function,⁴⁶ suggesting that the receptor’s tyrosine kinase is critical for EGFR-mediated tumor progression. This strategy has involved the random screening of small molecules or structures from natural or synthetic compound libraries for activities that compete for the Mg-ATP binding site of the catalytic domain of the EGFR tyrosine kinase.⁵⁹ Table 1 shows a partial list of the EGFR tyrosine kinase inhibitors that are in clinical development. The concentrations of these compounds that inhibit the EGFR kinase in vitro are in the nanomolar or subnanomolar range, whereas, in general, the concentrations required to inhibit the > 80%-homologous HER2/neu(erbB2) tyrosine kinase are a few logarithms higher (Table 1), supporting their overall EGFR specificity. In general, the 50% inhibitory concentration of these compounds against the EGFR was generated using the purified EGFR as a substrate in an in vitro kinase reaction. However, the methods to generate the 50% inhibitory concentration against the HER2 kinase are not comparable to those used for EGFR or not clearly described. Because of the high intracellular concentration of ATP, higher concentrations of these inhibitors are required to block EGFR phosphorylation continuously in intact cells (in vivo) than to inhibit the purified EGFR kinase in vitro. Nonetheless, this homology among HER receptors such as EGFR and HER2 has been exploited for the generation of bifunctional (EGFR-HER2) inhibitors such as CI1033, EKB-569, and GW2016. Chemical modification of some of these structures has led to the generation of irreversible inhibitors that bind covalently to specific cysteines in the ATP-binding pocket of the EGFR,⁶⁷ such as CI1033 and EKB-569. Although, theoretically, the irreversible inhibitors may be able to achieve a longer in situ half-life at their molecular target site, the efficacy (and possible enhanced toxicity) of this elegant approach compared with reversible EGFR kinase inhibitors requires further investigation.

CELLULAR MECHANISMS OF ACTION AND CLINICAL IMPLICATIONS
Several anti-EGFR antibodies, some in advanced phases of clinical development, have been reported.^52-55,69-72 Some of these are proposed to work, at least in part, by immune effector-mediated destruction of tumor cells.^53-55 In one study, neither mouse/human chimeric nor mouse monoclonal 225 antibodies inhibited growth of M24met melanoma cells in vitro. However, only the mouse monoclonal IgG activated mouse splenocytes and suppressed spontaneous M24 metastases in vivo,⁷³ further suggesting a role for ADCC on the antitumor effect of these therapies. This potential mechanism of action may not occur in cancer patients with suppressed immune function. Conversely, a possible role of ADCC suggests a rationale for combining EGFR antibodies with cytokines, eg, interleukin-2, that can enhance immune effector cells in cancer patients. If true, this immune mechanism of action may be unique to some EGFR antibodies and potentially provide an advantage over small molecule tyrosine kinase inhibitors.

Some but not all of these EGFR antibodies block ligand binding to the receptor’s EC domain. The ability to induce receptor dimerization, downregulation from the cell surface, and block the receptor’s catalytic function has been characterized best for the 528 mouse IgG2a, the 225 mouse IgG1, and the 225 humanized monoclonal antibodies.^47,48,52,71 However, as shown in Fig 3, the small-molecule inhibitors compete at the ATP binding site in the catalytic domain of the EGFR kinase. Despite these differences, both types of inhibitors can repress the network of cell cycle and apoptosis regulatory pathways altered by aberrant receptor signaling. EGFR-overexpressing transformed cells subvert the G1 to S transition by modulating the levels of cyclin D1 and the cyclin-dependent kinase (Cdk) inhibitor p27^Kip1 through both Ras/MAPK and PI3K/Akt signaling pathways.^3,74 Thus, not surprisingly, EGFR kinase inhibition with C225 or with ZD1839 upregulates p27 protein levels, leading to inhibition of Cdk-2 activity and tumor cell arrest in G1 phase.^62,75 In a recent study that used the anti-EGFR quinazoline AG1478, antisense p27 oligonucleotides decreased p27 and abrogated AG1478-induced G1 arrest of A431 cells.⁷⁶ These results suggest that upregulation of p27 and possibly restoration of Retinoblastoma protein (Rb) function are required for the antiproliferative effect of EGFR inhibitors. Thus, tumors with loss or low levels of p27, with cyclin D1 gene amplification, and/or with mutational inactivation of Rb may not respond to anti-EGFR therapies as well as cancers with wild-type Rb and normal levels of cyclin D1 and p27. This hypothesis can be tested prospectively in human trials with EGFR inhibitors.

It was reported recently that submicromolar concentrations of the EGFR-specific kinase inhibitor ZD1839 can block HER2 phosphorylation and growth of HER2-overexpressing breast cancer cells with moderate levels of EGFR.⁷⁷ In addition, the anti-EGFR quinazoline AG1478 suppressed mammary tumor formation in MMTV/TGF + MMTV/neu bigenic mice,⁷⁸ suggesting, with the previous clinical report, that EGFR kinase inhibitors can prevent EGFR-HER2/neu cooperation. A similar anti-EGFR quinazoline AG1517 induced the formation of inactive EGFR/HER2 heterodimers in HER2 gene-amplified SKBR-3 cells, preventing a response to the HER3/4 ligand heregulin.⁷⁹ This result supports an additional mechanism of action for small-molecule EGFR kinase inhibitors, ie, the potential ability to subtract HER2 from partnering with other HER receptors in a dominant-negative manner. Likewise, the C225 EGFR antibody augments the inhibitory effect of anti-HER2 antibodies in cells with high levels of HER2.⁸⁰ These data underscore the dynamic interactions of EGFR with other members of the HER network. It is naïve, though, to expect that blockade of the EGFR will universally inhibit HER2 function in cells that co-overexpress both kinases. In fact, in some experimental systems, the inactivation of HER2 is required to impair EGFR-mediated signaling and transformation.^81,82 Therefore, it is reasonable to speculate that in some EGFR-dependent tumors, the acquired overexpression of HER2 may counteract the antitumor effect of EGFR inhibitors.

In addition and similar to HER2, the cross-talk of tumor cell EGFR with heterologous receptors activated by neurotransmitters, lymphokines, and stress inducers⁸³ may alter the response to EGFR inhibitors. For example, ligand-activated G-protein–coupled receptors can indirectly cleave EGFR ligands, increasing their availability to cell surface EGFR. Second, G-protein–coupled receptors activate the Src kinase, which phosphorylates tyrosines in the carboxy-terminus of the EGFR and increases the receptor’s kinase activity in a ligand-independent manner.⁸⁴ Although based on solid basic science, the possibility that these EGFR-interactive networks may modulate the effect of EGFR inhibitors on tumor cells is only speculative at this point. Nonetheless, this possibility suggests that the EGFR should not be considered as a therapeutic target in isolation but as part of an interactive HER signaling network that, in turn, also receives inputs from other signaling networks.

Others have shown that both EGFR antibodies or small-molecule tyrosine kinase inhibitors reduce immunohistochemical levels of vascular endothelial growth factor, factor VIII staining, and/or microvessel density in tumors that regress after antireceptor therapy.^85-87 These results are consistent with the known dependence of the vascular endothelial growth factor promoter on EGFR signals and suggest that inhibition of tumor neoangiogenesis is an additional mechanism to explain the antitumor effect of EGFR inhibitors.

Finally, EGFR inhibitors have been combined with ionizing radiation and several standard anticancer drugs against tumor xenografts. The results of these studies suggest a supra-additive antitumor effect of the combination over either drug or radiation alone with no increased tumor host toxicity.^68,69,87-91 The biochemical/molecular mechanisms by which inhibition of EGFR signals modulates the response to cytotoxic chemotherapy (or vice versa) are not well established. This ability of EGFR inhibitors to sensitize cancer cells to several anticancer drugs, presumably with different molecular mechanisms of action, directly implicates the interruption of EGFR-mediated survival signals with the sensitization to nonspecific chemotherapy and possibly other cellular stresses. On the basis of these reports, it is unlikely that EGFR inhibition will preferentially sensitize to a particular drug or drugs over other chemotherapeutic agents. In some cases, these survival signals are enhanced further by the antitumor intervention itself. Exposure of EGFR-overexpressing tumor cells to ionizing radiation induces the release of TGF, increases tyrosine phosphorylation of EGFR, and activates MAPK and c-Jun NH₂-terminal kinase (JNK) pathways. Neutralization of TGF or inhibition of MEK1/2 sensitized the tumor cells to radiation.⁹²

Other studies support a link between EGFR signals and the ability of cells to repair double-strand DNA breaks. Inhibition of EGFR signaling with an EGFR antibody was accompanied by a reduction in levels of DNA-dependent protein kinase and its activity in the nucleus.⁹³ In irradiated SCC-1 and SCC-6 human squamous cancer xenografts, administration of C225 resulted in almost complete tumor regression, inhibition of postradiation damage repair, and redistribution of DNA-dependent protein kinase from the nucleus to the cytosol,⁸⁷ thus supporting a role for EGFR signals in protection from radiation-induced cell death and a novel mechanism of action of EGFR inhibitors. Although future studies undoubtedly will shed more light on the mechanisms by which chemotherapy or radiation interacts with EGFR inhibitors, these random combinations of standard anticancer drugs with EGFR inhibitors are practical. However, the possibility of encountering significant clinical toxicities from these empirical combinations as therapies become more prolonged and widespread should not be minimized.

REMAINING QUESTIONS
Both EGFR antibodies and small-molecule EGFR tyrosine kinase inhibitors are being actively tested in phase I, II, and III human trials. Most of these studies are being conducted in heavily pretreated patients with metastatic cancer, perhaps not the ideal population to test molecule-targeted, tumor-selective nontoxic drugs that may require prolonged administration to fully exert their antitumor effect. Despite this possible limitation, it is widely anticipated that inhibition of the EGFR network will alter the natural history of EGFR-expressing cancers. The results and interpretation of clinical studies with these inhibitors are beyond the scope of this section and will be covered by companion articles in this supplement. With the enormous clinical and laboratory research in the area of EGFR-targeted therapies, answers to many important questions are anticipated in the next few years. These include the mechanisms of action of and tumor cell resistance to EGFR inhibitors, the predictors of a clinical response in tumors, the optimal timing and duration of these therapies as well as the most appropriate end points in human trials, the possible role of these therapies in the prevention of cancer, the surrogate markers of EGFR inactivation in situ that will define optimal biologic (not maximum-tolerated) doses, the safer and more rational combinations with standard or other molecule-targeted treatments, and, most important, the potential adverse effects of prolonged inactivation of EGFR function in individuals with or without cancer.^{60, 61, 63-66}

	ACKNOWLEDGMENTS

 
Supported in part by National Institutes of Health grant no. R01 CA80195, the Susan G. Komen Breast Cancer Foundation, and Vanderbilt-Ingram Cancer Center support grant no. CA68485.

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