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At least 307 records · Page 17Linked to original sources
PubMed2005

EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients.

To determine whether EGFR tyrosine kinase domain mutations are early events in the pathogenesis of lung adenocarcinomas, we tested for the presence of EGFR mutations in histologically normal bronchial and bronchiolar epithelia from lung adenocarcinomas bearing the common EGFR mutations. DNA was extracted from microdissected tissue obtained from 21 tumors with known EGFR mutations, 16 tumors without mutation, and 90 sites of normal bronchial and bronchiolar epithelium from the same surgical specimens. With the use of PCR and direct DNA sequencing, EGFR mutations identical to the tumors were detected in the normal respiratory epithelium in 9 of 21 (43%) patients with EGFR mutant adenocarcinomas but none in patients without mutation in the tumors. The finding of mutations being more frequent in normal epithelium within tumor (43%) than in adjacent sites (24%) suggests a localized field effect phenomenon. Our findings indicate that mutation of the tyrosine kinase domain of EGFR is an early event in the pathogenesis of lung adenocarcinomas, and suggest EGFR mutations as an early detection marker and chemoprevention target.

Adenocarcinoma↗
PubMed2006

Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting.

PURPOSE: Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinoma (HNSCC) where expression levels correlate with decreased survival. Therapies that block EGFR have shown limited efficacy in clinical trials and primarily when combined with standard therapy. The most common form of mutant EGFR (EGFRvIII) has been described in several cancers, chiefly glioblastoma. The present study was undertaken to determine the incidence of EGFRvIII expression in HNSCC and the biological consequences of EGFRvIII on tumor growth in response to EGFR targeting. EXPERIMENTAL DESIGN: Thirty-three HNSCC tumors were evaluated by immunostaining and reverse transcription-PCR for EGFRvIII expression. A representative HNSCC cell line was stably transfected with an EGFRvIII expression construct. EGFRvIII-expressing cells and vector-transfected controls were compared for growth rates in vitro and in vivo as well as chemotherapy-induced apoptosis and the consequences of EGFR inhibition using the chimeric monoclonal antibody C225/cetuximab/Erbitux. RESULTS: EGFRvIII expression was detected in 42% of HNSCC tumors where EGFRvIII was always found in conjunction with wild-type EGFR. HNSCC cells expressing EGFRvIII showed increased proliferation in vitro and increased tumor volumes in vivo compared with vector-transfected controls. Furthermore, EGFRvIII-transfected HNSCC cells showed decreased apoptosis in response to cisplatin and decreased growth inhibition following treatment with C225 compared with vector-transfected control cells. CONCLUSIONS: EGFRvIII is expressed in HNSCC where it contributes to enhanced growth and resistance to targeting wild-type EGFR. The antitumor efficacy of EGFR targeting strategies may be enhanced by the addition of EGFRvIII-specific blockade.

Adult↗
PubMedDate not supplied

Modulation of EGFR gene transcription by a polymorphic repetitive sequence--a link between genetics and epigenetics.

The epidermal growth factor receptor (EGFR) plays a crucial role in growth, differentiation and motility of normal as well as tumor cells. The transduction of extracellular signals to the cytoplasm via the receptor not only depends on ligand binding, but is also determined by the receptor density on the cell surface. Therefore, with regard to cancer diagnosis and therapeutic approaches targeting EGFR it is important to know how the expression level of EGFR is controlled. We found that transcription activity declines with increasing numbers of CA dinucleotides of a highly polymorphic CA repeat in the first intron of the epidermal growth factor receptor gene. In vivo data from cultured cell lines support these findings, although other regulation mechanisms can compensate this effect. In addition, we showed that RNA elongation terminates at a site closely downstream of the simple sequence repeat (SSR) and that there are two separate major transcription start sites. Model calculations for the helical DNA conformation revealed a high bendability in the EGFR polymorphic region, especially if the CA stretch is extended. These data suggest that the CA-SSR can act like a joint, bringing the promoter in proximity to a putative repressor protein bound downstream of the CA-SSR. The data indicate that this polymorphism may be a marker for cancer, linking genetic and epigenetic risk factors. Furthermore, in breast cancer, heterozygous tumors with short CA-SSR showed an elevated EGFR-expression in contrast to tumours with longer CA-SSR. Tumours with loss of heterozygosity in intron 1 of egfr revealed an increased EGFR expression if the longer allele was lost. Moreover, decreased EGFR gene levels were significantly correlated with poor prognosis in breast cancer.

Biomarkers, Tumor↗
PubMed2005

EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment.

PURPOSE: It has been reported that EGFR mutations in lung carcinomas make the disease more responsive to treatment with tyrosine kinase inhibitors. We decided to evaluate the prevalence of EGFR mutations in a large series of non-small-cell lung carcinomas (NSCLCs) and to develop a rapid and sensitive screening method. PATIENTS AND METHODS We examined 860 consecutive NSCLC patients for EGFR mutations in exons 18, 19, and 21 using a dual technical approach--direct sequencing of polymerase chain reaction (PCR) products and PCR single-strand conformation polymorphism (SSCP) analysis. Moreover, all lung adenocarcinomas were analyzed for K-ras mutations at codon 12 by allele-specific oligoprobe hybriditations. RESULTS: There were no EGFR mutations in 454 squamous carcinomas and 31 large cell carcinomas investigated. Thirty-nine mutations were found in the series of 375 adenocarcinomas (10%). Mutations were present in 26% of 86 bronchioloalveolar carcinomas (BACs) and in 6% of 289 conventional lung adenocarcinomas; P = .000002. EGFR mutations and K-ras mutations were mutually exclusive. A multivariable analysis revealed that BAC histotype, being a never smoker, and female sex were independently associated with EGFR mutations (odds ratios: 4.542, 3.632, and 2.895, respectively). The SSCP analysis was accurate and sensitive, allowing identification of mutations that were undetectable (21% of cases) by direct sequencing. CONCLUSION: Mutations in the EGFR tyrosine kinase domain define a new molecular type of lung carcinoma, more frequent in particular subsets of patients. The SSCP assay is a rapid and reliable method for the detection of EGFR kinase domain mutations in lung cancer.

Adenocarcinoma↗
PubMed2001

EGFRs mediate chemotactic migration in the developing telencephalon.

Epidermal growth factor receptors (EGFRs) have been implicated in the control of migration in the telencephalon, but the mechanism underlying their contribution is unclear. We show that expression of a threshold level of EGFRs confers chemotactic competence in stem cells, neurons and astrocytes in cortical explants. This level of receptor expression is normally achieved by a subpopulation of cells during mid-embryonic development. Cells that express high levels of EGFR are located in migration pathways, including the tangential pathway to the olfactory bulb via the rostral migratory stream (RMS), the lateral cortical stream (LCS) leading to ventrolateral cortex and the radial pathway from proliferative zones to cortical plate. The targets of these pathways express the ligands HB-EGF and/or TGFalpha. To test the idea that EGFRs mediate chemotactic migration these pathways, we increased the size of the population of cells expressing threshold levels of EGFRs in vivo by viral transduction. Our results suggest that EGFRs mediate migration radially to the cortical plate and ventrolaterally in the LCS, but not tangentially in the RMS. Within the bulb, however, EGFRs also mediate radial migration. Our findings suggest that developmental changes in EGFR expression, together with changes in ligand expression regulate the migration of specific populations of cells in the telencephalon by a chemoattractive mechanism.

Animals↗
PubMed2002

Interaction between EGFR signaling and DE-cadherin during nervous system morphogenesis.

Dynamically regulated cell adhesion plays an important role during animal morphogenesis. Here we use the formation of the visual system in Drosophila embryos as a model system to investigate the function of the Drosophila classic cadherin, DE-cadherin, which is encoded by the shotgun (shg) gene. The visual system is derived from the optic placode which normally invaginates from the surface ectoderm of the embryo and gives rise to two separate structures, the larval eye (Bolwig's organ) and the optic lobe. The optic placode dissociates and undergoes apoptotic cell death in the absence of DE-cadherin, whereas overexpression of DE-cadherin results in the failure of optic placode cells to invaginate and of Bolwig's organ precursors to separate from the placode. These findings indicate that dynamically regulated levels of DE-cadherin are essential for normal optic placode development. It was shown previously that overexpression of DE-cadherin can disrupt Wingless signaling through titration of Armadillo out of the cytoplasm to the membrane. However, the observed defects are likely the consequence of altered DE-cadherin mediated adhesion rather than a result of compromising Wingless signaling, as overexpression of a DE-cadherin-alpha-catenin fusion protein, which lacks Armadillo binding sites, causes similar defects as DE-cadherin overexpression. We further studied the genetic interaction between DE-cadherin and the Drosophila EGF receptor homolog, EGFR. If EGFR function is eliminated, optic placode defects resemble those following DE-cadherin overexpression, which suggests that loss of EGFR results in an increased adhesion of optic placode cells. An interaction between EGFR and DE-cadherin is further supported by the finding that expression of a constitutively active EGFR enhances the phenotype of a weak shg mutation, whereas a mutation in rhomboid (rho) (an activator of the EGFR ligand Spitz) partially suppresses the shg mutant phenotype. Finally, EGFR can be co-immunoprecipitated with anti-DE-cadherin and anti-Armadillo antibodies from embryonic protein extracts. We propose that EGFR signaling plays a role in morphogenesis by modulating cell adhesion.

Animals↗
PubMed2003

Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR.

We have previously shown that CD82, a transmembrane protein of the tetraspanin superfamily is associated with EGFR and has a negative effect on EGF-induced signalling (Odintsova, E., Sugiura, T. and Berditchevski, F. (2000) Curr. Biol. 10, 1009-1012). Here we demonstrate that CD82 specifically attenuates ligand-induced dimerization of EGFR. The recombinant soluble large extracellular loop of CD82 has no effect on the dimerization thereby suggesting that other parts of the protein are required. Although CD82 is also associated with ErbB2 and ErbB3, ligand-induced assembly of the ErbB2-ErbB3 complexes is not affected in CD82-expressing cells. Furthermore, in contrast to the CD82-EGFR association, CD82-ErbB2 and CD82-ErbB3 complexes are stable in the presence of ErbB3 ligand. The effect of CD82 on the formation of EGFR dimers correlates with changes in compartmentalisation of the ErbB receptors on the plasma membrane. Expression of CD82 causes a significant increase in the amount of EGFR and ErbB2 in the light fractions of the sucrose gradient. This correlates with the increased surface expression of gangliosides GD1a and GM1 and redistribution of GD1a and EGFR on the plasma membrane. Furthermore, in CD82-expressing cells GD1a is co-localised with EGFR and the tetraspanin. Taken together our results offer a molecular mechanism of the attenuating activity of CD82 towards EGFR, whereby GD1a functions as a mediator of CD82-dependent compartmentalisation of the receptor.

Antigens, CD↗
PubMed2006

Tyrosine phosphorylation of p145met mediated by EGFR and Src is required for serum-independent survival of human bladder carcinoma cells.

Here we address the molecular mechanism of serum-independent survival and growth of human bladder carcinoma cell line 5637. Serum starvation promoted tyrosine phosphorylation of a 145-kDa protein and activation of the tyrosine kinase Src and the receptor for epidermal growth factor (EGFR) over a slow time course (>8 hours). The phosphorylated 145-kDa protein was identified as the beta-subunit of c-Met/hepatocyte growth factor (HGF) receptor, p145(met), in which tyrosine residues 1003, 1234, and 1235 were phosphorylated. Inhibitors of Src (PP2, SU6656) or EGFR (AG99), but not p145(met) (K252a), effectively blocked tyrosine phosphorylation of p145(met) and promoted cell death accompanied by activation of caspase-like proteases. Conditioned medium from the serum-starved 5637 cells or purified EGF readily promoted the activation of Src and EGFR, and tyrosine phosphorylation of p145(met) in normally grown 5637 cells, suggesting that autocrine signaling of EGFR ligands is responsible for signal transduction events in serum-starved cells. Consistent with this idea, a monoclonal antibody against EGFR that would interfere with the ligand binding to EGFR blocked tyrosine phosphorylation events and promoted the caspase activation and cell death in serum-free conditions. Such apoptotic cell death was also induced by pretreatment of cells with a high concentration of HGF that downregulated endogenous p145(met). Nevertheless, Cu2+ ions, competitive inhibitors for HGF-binding to p145(met), did not show any effect on cellular functions in serum-free conditions. These results suggest that the serum-independent growth of 5637 cells involves the transmembrane signaling cascade via EGFR ligand(s) (but not HGF), EGFR, Src and p145(met).

Amino Acid Sequence↗
PubMed2006

Significance of EGFR protein expression and gene amplification in non-small cell lung carcinoma.

We evaluated epidermal growth factor receptor (EGFR) protein expression by immunohistochemical analysis and EGFR gene amplification by fluorescence in situ hybridization in 199 consecutive newly diagnosed and surgically treated patients with primary non-small cell lung carcinoma (NSCLC) and correlated results with clinicopathologic findings. EGFR protein expression was more common in squamous cell carcinoma (SCC; 17 [26.2%]) than in adenocarcinoma (14 [11.1%]; (P = .0076) and more frequently associated with EGFR amplification (8 [14.5%] vs 4 [3.6%] cases; P = .0208). Poor differentiation was associated with a higher average number of EGFR gene copies per cell (mean, 4.18; P = .0322) and a higher EGFR/chromosome 7 ratio (mean, 1.84; P = .0324). N0 disease showed a higher number of EGFR gene copies (mean, 4.196; P = .0163). SCCs demonstrated a higher EGFR/chromosome 7 ratio than adenocarcinomas (mean, 1.95 vs 1.47; P = .0324), particularly T1 tumors (mean, 1.79; P = .0243). Statistical analysis failed to show correlation between outcome and EGFR protein expression and gene amplification in early NSCLC. EGFR protein expression was uncoupled from gene amplification in most cases, although good correlation occurred in a subset of SCCs.

Adenocarcinoma↗
PubMed2005

Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants.

BACKGROUND: Somatic mutations in the kinase domain of the epidermal growth factor receptor tyrosine kinase gene EGFR are common in lung adenocarcinoma. The presence of mutations correlates with tumor sensitivity to the EGFR inhibitors erlotinib and gefitinib, but the transforming potential of specific mutations and their relationship to drug sensitivity have not been described. METHODS AND FINDINGS: Here, we demonstrate that EGFR active site mutants are oncogenic. Mutant EGFR can transform both fibroblasts and lung epithelial cells in the absence of exogenous epidermal growth factor, as evidenced by anchorage-independent growth, focus formation, and tumor formation in immunocompromised mice. Transformation is associated with constitutive autophosphorylation of EGFR, Shc phosphorylation, and STAT pathway activation. Whereas transformation by most EGFR mutants confers on cells sensitivity to erlotinib and gefitinib, transformation by an exon 20 insertion makes cells resistant to these inhibitors but more sensitive to the irreversible inhibitor CL-387,785. CONCLUSION: Oncogenic transformation of cells by different EGFR mutants causes differential sensitivity to gefitinib and erlotinib. Treatment of lung cancers harboring EGFR exon 20 insertions may therefore require the development of alternative kinase inhibition strategies.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Modulation of EGFR gene transcription by secondary structures, a polymorphic repetitive sequence and mutations--a link between genetics and epigenetics.

The epidermal growth factor receptor (EGFR) plays a crucial role in growth, differentiation and motility of normal as well as tumor cells. The transduction of extracellular signals to the cytoplasm via the receptor not only depends on ligand binding, but is also determined by the receptor density on the cell surface. Therefore, in terms of cancer diagnosis and therapeutic approaches targeting EGFR it is decisive to know how the expression level of EGFR is controlled. We found that transcription activity declines with increasing numbers of CA dinucleotides of a highly polymorphic CA repeat in the first intron epidermal growth factor receptor gene. In vivo data from cultured cell lines support these findings, although other regulation mechanisms can compensate this effect. In addition, we showed that RNA elongation terminates at a site closely downstream of the simple sequence repeat (SSR) and that there are two separate major transcription start sites. Model calculations for the helical DNA conformation revealed a high bendability in the EGFR polymorphic region, especially if the CA stretch is extended. These data suggest that the CA-SSR can act like a joint bringing the promoter in proximity to a putative repressor protein bound downstream of the CA-SSR. The data suggest that this polymorphism is a marker for cancer linking genetic and epigenetic risk. Furthermore in breast cancer, heterozygous tumours with short CA-SSR showed an elevated EGFR-expression in contrast to tumours with longer CA-SSR. Tumours with loss of heterozygosity in intron 1 of egfr revealed an increased EGFR expression if the longer allele was lost. Moreover, deceased egfr gene dosages were significantly correlated to poor prognosis in breast cancer.

Animals↗
PubMed2005

Intrinsic and acquired resistance to EGFR inhibitors in human cancer therapy.

The epidermal growth factor receptor (EGFR) autocrine pathway plays a crucial role in human cancer since it contributes to a number of highly relevant processes in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. Among a variety of approaches used to target EGFR signaling, EGFR blocking monoclonal antibodies and small molecular weight EGFR tyrosine kinase compounds have been successfully developed. The results of a large body of preclinical studies and clinical trials suggest that targeting the EGFR could represent a significant contribution to cancer therapy. Both types of agent exert a significant antiproliferative activity when used alone or in combination with conventional antitumor treatments, such as chemotherapy or radiation therapy. Although the advanced clinical development of EGFR blocking drugs demonstrates their efficacy in some human metastatic diseases, such as lung, head and neck and colorectal cancers, the issue of constitutive resistance in a large number of patients and the development of acquired resistance in the responders remains an unexplored subject of investigation. Recent evidence suggests the role of specific activating mutations within the tyrosine kinase domain of EGFR to explain the dramatic responses to small molecule tyrosine kinase inhibitors in a subgroup of lung cancer patients. However, the intrinsic molecular mechanisms of resistance to these drugs are still unclear. This review will focus on the preclinical findings on therapeutic resistance to EGFR targeting agents.

Antineoplastic Agents↗
PubMedDate not supplied

Epidermal growth factor receptors (EGFR) localization in human testis.

An indirect immunofluorescence technique was used to detect and localize epidermal growth factor receptors (EGFR) in human testicular biopsies in different testicular diseases. Monolateral biopsies from twelve infertile subjects were studied from qualitative/quantitative points of view and were examined by immunofluorescence study with anti-EGFR monoclonal antibody. Two different patterns of EGFR expression were observed: a very weak presence of EGFR was detectable on Sertoli cells, peritubular basal structures, and interstitial compartment in testicular biopsies showing a normal spermatogenic status; and an important increase in EGFR expression was observed on the cytoplasm of Sertoli cells and on peritubular basal structures in biopsies exhibiting various degrees of hypospermatogenesis and in a case of Sertoli cells only syndrome. Germ cells did not show EGFR immunolocalization. EGFR seems to be present on different testicular target cells. EGFR expression increases on peritubular and Sertoli cells in the presence of significant tubular damage.

Adult↗
PubMed1998

A study on the relationship between antisense EGFR cDNA fragments and nuclear matrix proteins in glioblastoma cells.

The association of antisense epidermal growth factor receptor (EGFR) cDNA fragments with nuclear matrix from EGFR-antisense transfected glioblastoma cell lines U343 and U87 was investigated. A 1015 bp DNA fragment (primer I-II) was amplified in both genomic DNA and nuclear matrix-associated DNA (NM DNA) from EGFR-antisense transfected glioblastoma cell lines U343E and U87E. Two different DNA fragments (940 bp and 110 bp) were amplified by primer I-III in both genomic DNA and NM DNA of U343E, while one 110 bp PCR product was shown with the same primer in both genomic DNA and NM DNA of U87E only. After EGFR-antisense transfection, the binding property of the 110 bp DNA fragment (primer IV-V) to nuclear matrix was not affected. Southwestern blotting demonstrated the presence of antisense EGFR cDNA binding nuclear matrix proteins. Our findings demonstrate that not only EGFR DNA is associated with nuclear matrix, but the transfected antisense EGFR cDNA also binds to nuclear matrix proteins. The nuclear matrix is most likely involved in the replication and transcription of antisense EGFR cDNA or hybridisation with sense mRNA in vitro.

Brain Neoplasms↗
PubMed2000

Profile of epidermal growth factor receptor (EGFr) expression in human malignancies: effects of exposure to EGF and its biological influence on established human tumour cell lines.

The aim of this study was to compare the profile of EGFr expression in transitional cell carcinoma of the bladder (TCC) and in oral squamous cell carcinoma (OSCC). In addition, to study the influence of EGF stimulation on the expression of major histocompatibility complex class I antigens, placental alkaline phosphatase (PLAP) as well as changes in tumour cell sensitivity to cisplatin using immunocytochemical staining, a colorimetric assay and SDS-gel electrophoresis. The results showed that: a) strong EGFr expression could be seen in 22/88 (27%) cases of TCCs. In oral tumours the values for non-invasive ameloblastoma and invasive OSCC were 4/25 (16%) and 30/41 (73%) respectively. b) EGFr expression in tumour cell lines paralleled that of tumour biopsies. The number of lines expressing high and low EGFr expression amongst TCCs were 4 and 4 and in OSCCs were 3 and 1 respectively. c) Exposure of tumour cell lines to EGF led to: i) an increase in EGFr expression (stimulatory indices SI, ranged from 1.06 to 2.58) for TCCs but a decrease in the case of OSCCs (SI ranged from 0.01 to 0.85). The corresponding SI values for class I antigens were 0.95-1.16 and 0.10-0.84. ii) A significant reduction in expression of PLAP by OSCC cell lines. iii) An increased susceptibility of OSCC cell lines to cisplatin by as much as 14% (p<0.001). These data demonstrated the overexpression of EGFr in a significant proportion of TCCs. As for oral tumours it depended on whether they were of an invasive or non-invasive type. In the invasive cases the majority overexpressed EGFr. The exposure of OSCC but not TCC tumour cells to EGF resulted in down regulation of EGFr and class I antigens. The expression of PLAP was also significantly reduced. Exposure of OSCC cells to EGF resulted in their increased susceptibility to cisplatin. The data supports the notion that the mitogenic activation of some tumour cells by EGF resulted in a reduction of their immune visibility, differentiation status and an increase in chemosensitivity.

Alkaline Phosphatase↗
PubMed2005

Conditional EGFR promotes cell cycle progression and prevention of apoptosis in the absence of autocrine cytokines.

v-ErbB is an oncogene related to the Epidermal Growth Factor Receptor (EGFR). EGFR overexpression has been observed in many pathological situations. There is a truncated form of EGFR, referred to as EGFvIII, which resembles v-ErbB in biological properties and is often expressed in certain human tumors. Aberrant EGFR expression in human cancers is often constitutive and may occur in the presence of mutated oncogenes or tumor suppressor genes. To circumvent these problems, we subcloned v-ErbB into a vector which contains the estrogen receptor hormone binding domain (ER) which renders the v-ErbB:ER protein dependent upon beta-estradiol for activity. v-ErbB:ER conditionally abrogated the cytokine dependence of hematopoietic cells more efficiently than activated v-Ha-Ras, v-Src, Raf or Akt. Abrogation of cytokine-dependence by v-ErbB:ER was not due to the synthesis of autocrine growth factors. Treatment of v-ErbB:ER cells with the EGFR inhibitor AG1478 efficiently induced apoptosis. Induction of apoptosis and prevention of cell cycle progression by the EGFR inhibitor were only observed when the cells were grown in response to v-ErbB:ER activation demonstrating specificity. In contrast, the other inhibitors suppressed cell cycle progression when the cells were grown in response to v-ErbB:ER or the cytokine interleukin-3. When MEK and either EGFR or PI3K/mTOR inhibitors were added, an enhanced apoptotic response was observed. Thus this conditional ErbB construct is useful to elucidate EGFR signaling and anti-apoptotic pathways in the absence of autocrine cytokine expression.

Animals↗
PubMedDate not supplied

Enhancement of chemosensitivity and programmed cell death by tyrosine kinase inhibitors correlates with EGFR expression in non-small cell lung cancer cells.

Epidermal growth factor receptor (EGFR) is a 170 kD transmembrane glycoprotein with tyrosine kinase activity. Overexpression of the EGFR has been detected in many human cancers, including non-small cell lung cancer (NSCLC), and is correlated with poor prognosis and chemoresistance. We investigated the effects of tyrosine kinase inhibitors on chemosensitivity and chemotherapeutic drug-induced programmed cell death in NSCLC cell lines that express different levels of EGFR. NCI-H596 cells, which strongly express EGFR, were more resistant to the growth inhibitory effects of cisplatin, doxorubicin and etoposide than were NCI-H358 cells, which only weakly express EGFR. Both genistein, a general tyrosine kinase inhibitor, and tyrphostin AG 1478, a tyrosine kinase inhibitor specific for EGFR, inhibited phosphorylation of EGFR in NCI-H596. Combinations of genistein or tyrphostin AG 1478 with cisplatin, doxorubicin, or etoposide enhanced the antiproliferative effects and induced programmed cell death in NCI-H596 cells, whereas no such additive effects were observed in NCI-H358 cells. The programmed cell death induced by these agents involved CPP32 mediated PARP cleavage and DNA fragmentation. These results indicate that tyrosine kinase inhibitors in combination with chemotherapeutic drugs may prove to be a viable therapeutic strategy for the treatment of those types of NSCLC that demonstrate strong expression of EGFR.

Antineoplastic Agents↗
PubMed1999

Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members.

In a series of 111 patients with squamous cell carcinoma (SCC), we used immunohistochemistry to examine the expression levels of four epidermal growth factor receptor (EGFR) family members (EGFR, HER-2/neu, HER-3, and HER-4). Expression of the EGFR members was not significantly associated with tumor size. However, their expressions (except for HER-4) were significantly associated with the presence of lymph node metastasis, and all of them were significantly associated with distant metastasis. We further examined the association between the expression levels of the EGFR members and the survival rates in 47 oral SCC patients whose detailed clinical follow-ups were available. The expression of all EGFR members was significantly associated with shortened patient survival, and the association was strongest for HER-2/neu. Furthermore, the combination of HER-2, HER-3, and EGFR but not HER-4 significantly improved the predicting power. The expression level of HER-2/neu was significantly correlated with that of EGFR or HER-3. Similar coexpression patterns were also observed in three oral SCC cell lines studied, but not in four other head and neck SCC cell lines. Taken together, these results indicated that expression levels of EGFR, HER-2/ neu, and HER-3 may help predict the outcome of patients with oral SCC.

Adolescent↗