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Dipartimento di Endocrinologia Molecolare e Clinica, Università degli Studi di Napoli ‘Federico II’, Naples, Italy
1 Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale ‘F. Magrassi e A. Lanzara’, Seconda Università degli Studi di Napoli, Naples, Italy
(Requests for offprints should be addressed to F Ciardiello; Email: fortunato.ciardiello{at}unina2.it)
This paper was presented at the 1st Tenovus/AstraZeneca Workshop, Cardiff (2005). AstraZeneca has supported the publication of these proceedings.
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Abstract |
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 Top Abstract IntroductionMechanisms of resistance to...Activation of alternative growth...Activation of EGFR-independent,...Independent activation of...Effects of EGFR gene...Other mechanisms of cancer...ConclusionsReferences |
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Introduction |
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TopAbstractIntroductionMechanisms of resistance to...Activation of alternative growth...Activation of EGFR-independent,...Independent activation of...Effects of EGFR gene...Other mechanisms of cancer...ConclusionsReferences |
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Overexpression of EGFR correlates with poor prognosis and worse clinical outcome in a large number of malignancies, including NSCLC, bladder, breast and HNSC cancers (Moscatello et al. 1995, Grandis et al. 1998). Nicholson and colleagues (Nicholson et al. 2001) reviewed 200 studies involving more than 20 000 patients to determine the prognostic value of increased EGFR expression for reduced recurrence-free or overall survival rates and found a strong prognostic value for HNSCC, ovarian, bladder, cervical and esophageal cancers, a moderate prognostic value for CRC, breast, gastric and endometrial tumors, and only a weak prognostic value for NSCLC. Moreover, increased receptor content is often associated with an increased production of specific activating ligands, such as transforming growth factor 
(TGF), by the same tumor cells, leading to receptor activation through an autocrine stimulatory pathway (Rusch et al. 1993, Salomon et al. 1995, Grandis et al. 1998).
Several strategies for EGFR targeting have been proposed, including small molecule tyrosine kinase inhibitors (TKIs) that interfere with receptor phosphorylation, monoclonal antibodies (MAbs) that directly interfere with ligand-receptor binding, antisense oligonucleotides or ribozymes that block mRNA receptor translation in a functioning protein (Yamazaki et al. 1998, Ciardiello et al. 2001a) and, finally, MAbs which serve as carriers of radionuclides, prodrugs or toxins (Azemar et al. 2000). Of these approaches, low-molecular weight TKIs and blocking MAbs are in the most advanced stages of clinical development (Ciardiello & Tortora 2001). MAbs function at the extracellular ligand-binding site of the EGFR, whereas small molecule TKIs function at the intracellular tyrosine kinase domain of the EGFR. The efficacy in cancer treatment of some of these inhibitors is testified by a massive amount of preclinical data and by clinical trials in advanced chemorefractory cancers, including HNSCC, NSCLC and CRC. These data have led to the recent introduction into clinical practice of cetuximab (Erbitux), a chimerized human-murine IgG1 anti-EGFR blocking MAb, which has been approved for irinotecan-refractory, metastatic colorectal cancer, and of two low molecular weight synthetic, selective EGFR-TKIs, gefitinib (Iressa) and erlotinib (Tarceva), which have been licensed for the second and third line treatment, respectively, of advanced chemorefractory NSCLC.
Despite high levels of EGFR expression within the tumor, some patients are clearly refractory to EGFR inhibitor treatment, suggesting that mere EGFR expression is not a reliable predictor of response to therapy and revealing the emerging importance of understanding the molecular mechanisms responsible for cancer cell resistance to such inhibitors. A preclinical study on 60 human cancer cell lines of the United States National Cancer Institute Anticancer Drug Screen has been performed with several EGFR family inhibitors (Bishop et al. 2002) and has revealed that the level of EGFR expression for a specific tumor is less important than the degree of activation of the EGFR-dependent intracellular pathways in predicting the response to EGFR-targeted therapy. In fact, EGFR activation can be affected from several factors, such as receptor homo- or hetero-dimerization with each of the other three members of the EGFR family (ErbB-2, ErbB-3 or ErbB-4), increased expression of different ligands and EGFR mutations (Arteaga 2002). The lack of a simple relationship between the levels of EGFR expression and the degree of its activation renders it difficult to predict the clinical effectiveness of EGFR targeted therapeutics (Arteaga & Baselga 2003) (Table 1
). For such reasons, the investigation of the molecular mechanisms which predict for sensitivity or which lead to resistance to EGFR signal transduction inhibitors is an important and clinically relevant field of cancer research.
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Mechanisms of resistance to EGFR inhibitors |
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TopAbstractIntroductionMechanisms of resistance to...Activation of alternative growth...Activation of EGFR-independent,...Independent activation of...Effects of EGFR gene...Other mechanisms of cancer...ConclusionsReferences |
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Activation of alternative growth factor receptor signaling pathways |
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TopAbstractIntroductionMechanisms of resistance to...Activation of alternative growth...Activation of EGFR-independent,...Independent activation of...Effects of EGFR gene...Other mechanisms of cancer...ConclusionsReferences |
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The relationship between increased IGF-IR activity and the efficacy of small molecule EGFR-TKIs, such as the quinazoline derivative AG1478, has been investigated in human glioblastoma multiforme (GBM) cell lines (Chakravarti et al. 2002). In this study, despite equivalent EGFR levels and a similar reduction in EGFR signaling, as measured by EGFR tyrosine phosphorylation, following treatment with AG1478 the antiproliferative activity of EGFR blockade was different in various GBM cell lines. In fact, AG1478 was able to induce apoptosis and to reduce invasive potential only in sensitive GBM cell lines. The resistant phenotype correlated in GBM cancer cells with enhanced IGF-IR levels following AG1478 administration and with sustained signaling through the PI3K-akt pathway. In fact, the small molecule EGFR TKI AG1478 failed to inhibit the phosphorylation and activation of the antiapoptotic effector Akt GBM resistant cells, whereas it induced a significant reduction in PI3K and akt activition in GBM sensitive cells. In this study, combined targeting of IGF-IR and EGFR by using AG1478 and AG1024, a specific IGF-IR inhibitor, greatly enhanced apoptosis and reduced the invasive potential of GBM resistant cells (Chakravarti et al. 2002). More recently, a correlation between IGF-IR activation and acquired resistance to EGFR blockade was also demonstrated for breast and prostate cancer cell lines (Jones et al. 2004). Continuous exposure to gefitinib for up to 6 months of the EGFR-positive, gefitinib-sensitive, tamoxifen-resistant, MCF- 7 breast cancer cells (TAM-R) caused the occurrence of a stable, gefitinib-resistant subline (TAM/TKI-R). As compared with parental TAM-R cells, the TAM/ TKI-R cells showed no detectable basal phosphorylated EGFR activity, but elevated levels of IGF-IR, protein kinase C (PKC) and Akt. Treatment of the gefitinib-resistant TAM/TKI-R cell line with the specific IGF-IR inhibitor AG1024 resulted in significant growth inhibition and in reduced migratory capacity. Similarly, a gefitinib-resistant variant of the EGFR-positive, gefitinib-sensitive, androgen-independent human prostate cancer cell line DU145 has been generated by selective drug pressure following long-term exposure to gefitinib (DU145/TKI-R cells). Also in this case, the EGFR-resistant phenotype was associated with an increased signaling via the IGF-IR pathway (Jones et al. 2004).
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Activation of EGFR-independent, tumor-induced angiogenesis |
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TopAbstractIntroductionMechanisms of resistance to...Activation of alternative growth...Activation of EGFR-independent,...Independent activation of...Effects of EGFR gene...Other mechanisms of cancer...ConclusionsReferences |
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The impact of VEGF signaling in cancer cell resistance in EGFR-expressing tumors has been investigated in our laboratory through the generation of human GEO colon cancer cell lines resistant to either small molecule EGFR-TKIs, such as gefitinib, or to anti-EGFR MAbs, such as cetuximab (Ciardiello et al. 2004). GEO cell resistant sublines have been established from GEO xenografts growing in nude mice which were treated chronically with one of these two EGFR inhibitors. After an initial tumor regression, almost all the treated animals experienced tumor regrowth at the site of inoculation after a variable latency period despite continuous therapy with the EGFR inhibitor. In contrast, continuous treatment of mice bearing GEO xenografts with ZD6474, a small molecule VEGF .k-1/KDR (VEGFR-2) tyrosine kinase inhibitor that also has activity against the EGFR tyrosine kinase, resulted in efficient tumor growth inhibition for the entire duration of treatment (up to five months). Interestingly, sequential ZD6474 treatment of GEO tumor xenografts following cetuximab or gefitinib resulted in the block of tumor growth, in contrast to re-treatment with either selective anti- EGFR agent. Cell lines derived from such resistant tumors (named GEO-C225-RES and GEO-ZD1839- RES for resistance to cetuximab or to gefitinib, respectively) have been characterized. Protein expression analysis revealed no major changes in the expression of cell membrane EGFR or of the EGFR ligand TGF, of Bcl-2, Bcl-XL, p53, MDM2, Akt, activated Akt, and MAPK. However, both GEOC225- RES and GEO-ZD1839-RES cells exhibited a 5- to 10-fold increase in activated phospho-MAPK, in the expression of cyclooxygenase-2 (COX-2) and of VEGF as compared with parental EGFR-inhibitor sensitive GEO cells. GEO-C225-RES and GEO-ZD1839-RES growth as xenografts in nude mice was not significantly affected by treatment with either cetuximab or gefitinib but was efficiently inhibited by ZD6474. These data confirm the previous reported experimental evidence by which acquired resistance to EGFR antagonists might arise from enhanced VEGF expression rather than loss in the expression or a functional alteration of EGFR signaling. However, the balance between VEGF and EGFR receptors signaling in causing and sustaining resistance to EGFR inhibitors appears to be also dependent on tumor cell type. In this respect, a gefitinib-resistant lung adenocarcinoma cell line (PC-9/ ZD) has been recently characterized with a similar profile of lack of sensitivity to both gefitinib and ZD6474 in vivo as compared with gefitinib- and ZD6474- sensitive PC-9 parental cells, suggesting the activation of other EGFR-independent biochemical pathways which are responsible for the resistant phenotype (Taguchi et al. 2004).
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Independent activation of intracellular molecular effectors which function downstream to the EGFR |
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TopAbstractIntroductionMechanisms of resistance to...Activation of alternative growth...Activation of EGFR-independent,...Independent activation of...Effects of EGFR gene...Other mechanisms of cancer...ConclusionsReferences |
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Effects of EGFR gene mutations and of the loss of the target |
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TopAbstractIntroductionMechanisms of resistance to...Activation of alternative growth...Activation of EGFR-independent,...Independent activation of...Effects of EGFR gene...Other mechanisms of cancer...ConclusionsReferences |
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Furthermore, GBM cell lines expressing the mutated variant EGFR-vIII appear to be relatively resistant to gefitinib since higher doses and longer exposure to gefitinib are necessary to signifcantly decrease EGFRvIII phosphorylation. Cell cycle analysis shows that nascent DNA synthesis in EGFR-expressing cells is inhibited in a dose-dependent manner by gefitinib, whereas it is unaffected in EGFRvIII-expressing cells. The protective activity of EGFRvIII may be due in part to phosphorylation of Akt, which is inhibited in EGFR expressing cells after treatment with gefitinib, but is unaffected in cells expressing EGFRvIII (Learn et al. 2004).
However, a large body of clinical data has been recently provided on the predictive role of EGFR gene mutations and enhanced sensitivity to EGFR inhibitors. Recent landmark publications have shown that specific somatic mutations in the kinase domain of EGFR in some some patients with advanced and chemorefractory NSCLC are associated with dramatic and long lasting clinical responses to the tyrosine kinase inhibitor gefitinib. These mutations in the EGFR seem to play a significant role in determining the sensitivity of tumor cells to small molecule EGFR-TKIs such as gefitinib and erlotinib by altering the tridimensional conformation and activity of the receptor. Paez and colleagues (Paez et al. 2004) searched for somatic genetic alterations in a set of 119 primary NSCLC tumors by sequencing the EGFR gene. Somatic mutations (missense mutations G719S and L858R and Del-1 deletion) were found in the EGFR kinase domain and correlated strikingly with specific patient characteristics since mutations were more frequent in adenocarcinomas (21%) than in other NSCLCs (2%), more frequent in women (20%) than in man (9%), and more frequent in Japanese patients. The highest proportion of EGFR mutations were observed in Japanese women with adenocarcinoma (57%). More interestingly, the patient characteristics that correlate with the presence of EGFR mutations were the same that correlate with clinical response to gefitinib. H3255 cells, a lung adenocarcinoma cell line with the EGFR L858R mutation, demonstrates high sensitivity to growth inhibition induced by gefitinib, whereas three other NSCLC cell lines (H1781, H1666 and H441 cells) expressing wild type EGFR are resistant to these EGFR antagonist. In H3255 cells, treatment with gefitinib completely inhibits EGFR autophosphorylation, as well as blocking the phosphorylation of known downstream targets of EGFR such as ERK1/2 and Akt. In contrast, the other three cell lines show comparable levels of inhibition of EGFR phosphorylation only when gefitinib is present at concentrations roughly 100 times higher.
Lynch and colleagues (Lynch et al. 2004) sequenced the entire coding region of the gene using PCR amplification of individual exons. Heterozygous mutations were observed in eight of nine patients defined as responders to gefitinib, all of which were clustered within the tyrosine kinase domain of EGFR. Four tumors had in-frame deletions within exon 19, another four tumors had amino acid substitutions within exon 21 of the tyrosine kinase domain. By comparison, no EGFR mutations were observed in seven patients with non small cell lung cancer who had no response to gefitinib. To study the functional properties of the EGFR encoded by these mutated genes, EGFR with the L747–P753 in-frame deletion and EGFR with the L858R missense mutation were expressed in Cos-7 cells. In the absence of serum and of activating growth factors, neither wild-type nor mutant EGFR demonstrated autophosphorylation. However, EGF treatment caused a three- to four-fold increase in EGFR phosphorylation in both mutant EGFRs as compared with the activation of the wild-type EGFR. Moreover, the two mutant receptors had a continued activation for up to three hours. Remarkably, both mutant receptors were more sensitive than the wildtype receptor to inhibition by gefitinib. Since all the mutations are clustered near the ATP cleft of the tyrosine kinase domain, where they flank amino acids shown in crystallographic studies to mediate binding of 4-anilinoquinazoline compounds, such as gefitinib (Stamos et al. 2002), it is possible that the mutations result in repositioning of these critical residues, stabilizing their interaction with both ATP and its competitive inhibitor gefitinib. Such a mechanism could explain both the increased receptor activation after ligand binding and the enhanced inhibition induced by gefitinib. The effects of mutated variants of EGFR has also been investigated in other NSCLC cell lines, such as H1650, that carries the in-frame deletion E746-A750, or H1975, with missense mutation L858R, or NCI358, H1666 and H1734 that have wildtype EGFR (Sordella et al. 2004). Cell lines harbouring EGFR mutations displayed a selective activation of anti-apoptotic signals through Akt and signal transduction and activator of transcription (STAT) 5, which promote cell survival but have no effect on Erk, which induces proliferation. EGF-induced autophosphorylation of tyrosine992 (Y992) and tyrosine1068 (Y1068) was markedly elevated in the two cancer cell lines harboring EGFR gene mutations, with a concomitant increase in phosphorylation of Akt and STAT5 but not of Erk. The two lung cancer cell lines harboring EGFR mutations exhibited an increased proliferative activity as relative to lung cancer cells expressing wild-type EGFR when maintained in the presence of EGF in low serum concentrations. However, the proliferation rate and cell density at confluence were comparable at normal serum concentrations. Moreover, NSCLC cells expressing mutant EGFRs underwent extensive apoptosis after small interfering RNA (siRNA)–mediated knockdown of the mutant EGFR or treatment with pharmacological inhibitors of Akt and STAT signaling and were relatively resistant to apoptosis induced by conventional chemotherapeutic drugs, such as doxorubicin and cisplatin. Thus, these mutant EGFRs selectively transduce survival signals on which NSCLCs become dependent and it is possible that NSCLCs expressing only wild-type receptors do not display a similar dependence on EGFR activation and this could account for the relative gefitinib-insensitivity of human NSCLC that express wild-type EGFR.
Somatic mutations in the EGFR TK domain have also been associated with sensitivity to erlotinib (Pao et al. 2004). Five of seven NSCLC tumor specimens from patients which were sensitive to erlotinib treatment had analogous somatic mutations (in-frame deletions within exon 19 or point mutations within exon 21), as opposed to no mutations found in 10 erlotinib-refractory tumors. Most EGFR mutation-positive tumors were adenocarcinomas from patients who have never smoked.
The issue of EGFR mutations in sensitivity/resistance to EGFR inhibitors has been addressed also for non-selective EGFR antagonists, such as ZD6474 (Arao et al. 2004). A strong correlation has been noted in several cancer cells lines in vitro between the IC50 values of gefitinib and ZD6474; conversely no correlation was observed between the sensitivity to ZD6474 and the level of EGFR or VEGFR expression. The NSCLC cell line PC-9 was hypersensitive to gefitinib and ZD6474, and a small (15-bp) in-frame deletion of the ATP-binding site (exon 19) in the EGFR TK domain was detected (delE746-A750–type deletion). The involvement of this EGFR mutation in the cellular sensitivity to ZD6474 has been confirmed by transfection of HEK293 cells with the EGFR mutated construct. These cells exhibited a 60-fold higher sensitivity to ZD6474 as compared with cells expressing wild-type EGFR. ZD6474 inhibited the phosphorylation of the mutant EGFR by 10-fold as compared with cells with wild-type EGFR. The correlation between ‘gain of function’, somatic EGFR mutations and sensitivity to small molecule EGFR-TKIs has been documented in NSCLC cell lines and patients. However, similar mutations have not been found or appear to be very rare in other cancer types, including breast, glioblastomas, CRC and HNSCC (Barber et al. 2004, Lynch et al. 2004, Lee et al. 2005).
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Other mechanisms of cancer cell resistance to EGFR inhibitors |
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TopAbstractIntroductionMechanisms of resistance to...Activation of alternative growth...Activation of EGFR-independent,...Independent activation of...Effects of EGFR gene...Other mechanisms of cancer...ConclusionsReferences |
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Recently, proteome pattern studies have been performed to understand the cellular signals underlying resistance to MAbs against EGFR. To define proteins involved in EGFR-triggered growth regulation and potential resistance mechanisms, the proteome profile of human colorectal cancer cell lines with high expression of functional EGFR but different sensitivity to cetuximab has been characterized (Skvortsov et al. 2004). Cetuximab treatment resulted in a complete saturation of EGFR in Caco-2 and HRT-18 CRC cell lines. However, whereas Caco-2 cells showed inhibition of proliferation, growth of HRT-18 cells was not suppressed. Using two-dimensional electrophoresis gels and subsequent mass spectrometry, the authors identified 14 proteins differentially expressed in the two cell lines. Among these proteins, fatty acid binding protein and heat shock protein 27 might contribute to the resistance of HRT-18 CRC cells to cetuximab treatment. These data demonstrate that proteome-based investigations could be an useful tool to better understand the complex protein interactions involved in EGFR signaling and in resistance to EGFR inhibitors.
Sensitivity to EGFR antagonists could be also related to genetic differences among individuals. The hypothesis that genetic variations in the EGFR gene could explain the resistant phenotype has been tested (Amador et al. 2004). In fact, several studies have revealed that polymorphic variations in genes encoding drug targets affect the response and toxicity to therapeutic agents (Arranz et al. 1995, Yoshida et al. 1995, Benetos et al. 1996, van Essen et al. 1996, Henrion et al. 1998, Lima et al. 1999). The EGFR gene contains a highly polymorphic sequence in intron 1, which consists of a variable number of CA dinucleotide repeats ranging from 9 to 21 (Chrysogelos 1993). This sequence has been shown to affect the efficiency of gene transcription such that subjects or cell lines with a greater number of CA repeats have lower levels of EGFR mRNA and protein expression (Gebhardt et al. 1999, Buerger et al. 2000). HNSCC lines with lower numbers of CA dinucleotides in the CA single sequence repeat (CA-SSR) of the intron 1 had a higher expression of EGFR and were more sensitive to the growth inhibitory effects of erlotinib. Phenotypic modification by silencing EGFR mRNA expression in HN029 cells sensitive to erlotinib induced resistance to this drug. The analysis of clinical specimens obtained from tumor and paired peripheral blood cells from 30 patients with advanced HNSCC revealed an equivalent number of CA dinucleotides between paired samples of the same individual, supporting the notion that this region is not commonly somatically mutated in the process of tumor development.
For some common anticancer agents, one possible mechanism of resistance is increased drug efflux resulting from the activity of membrane-associated pumps, such as P-glycoprotein (P-gp), the product of the multidrug resistance gene mdr-1. Since many small molecule inhibitors of tyrosine kinase have a neutral and hydrophobic nature, they could be substrates for P-gp or similar-acting efflux pumps. Intracellular accumulation of CI-1033, a small molecule EGFR-TKI, seems to be dependent on the breast cancer resistance protein (BCRP), a recently cloned ATP binding cassette transporter. In MDA-MB-231 breast cancer cells, transfection of BCRP resulted in a decrease in CI-1033 accumulation, compared with cells transfected with empty vector s(Erlichman et al. 2001). This observation suggests that CI-1033 is itself a substrate for BCRP, which in turn could possibly regulate the efflux of other specific EGFR inhibitors.
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Conclusions |
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TopAbstractIntroductionMechanisms of resistance to...Activation of alternative growth...Activation of EGFR-independent,...Independent activation of...Effects of EGFR gene...Other mechanisms of cancer...ConclusionsReferences |
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Acknowledgements |
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TopAbstractIntroductionMechanisms of resistance to...Activation of alternative growth...Activation of EGFR-independent,...Independent activation of...Effects of EGFR gene...Other mechanisms of cancer...ConclusionsReferences |
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