• Proceedings of the Korean Society of Life Science Conference
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• 2007.10a
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• pp.95.2-95.2
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• 2007

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• Journal of Microbiology and Biotechnology
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• v.31 no.4
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• pp.559-569
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• 2021

As one of the major types of lung cancer, non-small cell lung cancer (NSCLC) accounts for the majority of cancer-related deaths worldwide. Treatments for NSCLC includes surgery, chemotherapy, and targeted therapy. Among the targeted therapies, resistance to inhibitors of the epidermal growth factor receptor (EGFR) is common and remains a problem to be solved. MET (hepatocyte growth factor receptor) amplification is one of the major causes of EGFR-tyrosine kinase inhibitor (TKI) resistance. Therefore, there exists a need to find new and more efficacious therapies. Deoxypodophyllotoxin (DPT) extracted from Anthriscus sylvestris roots exhibits various pharmacological activities including anti-inflammation and anti-cancer effects. In this study we sought to determine the anti-cancer effects of DPT on HCC827GR cells, which are resistant to gefitinib (EGFR-TKI) due to regulation of EGFR and MET and their related signaling pathways. To identify the direct binding of DPT to EGFR and MET, we performed pull-down, ATP-binding, and kinase assays. DPT exhibited competitive binding with ATP against the network kinases EGFR and MET and reduced their activities. Also, DPT suppressed the expression of p-EGFR and p-MET as well as their downstreat proteins p-ErbB3, p-AKT, and p-ERK. The treatment of HCC827GR cells with DPT induced high ROS generation that led to endoplasmic-reticulum stress. Accordingly, loss of mitochondrial membrane potential and apoptosis by multi-caspase activation were observed. In conclusion, these results demonstrate the apoptotic effects of DPT on HCC827GR cells and signify the potential of DPT to serve as an adjuvant anti-cancer drug by simultaneously inhibiting EGFR and MET.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.1
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• pp.233-237
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• 2015

Background: Lung cancer is the leading cause of cancer death in Brunei Darussalam, accounting for almost 20% of the total. The epidermal growth factor receptor (EGFR) is a member of the erbB family of tyrosine kinase receptor proteins, which includes c-erbb2(HER2/neu), erb-B3, and erb-B4. EGFR overexpression is found in a third of all epithelial cancers, often associated with a poor prognosis. Materials and Methods: Protein expression of EGFR in 27 cases of lung cancer tissue samples and 9 cases of normal lung tissue samples was evaluated using an immunohistochemical approach. Results: The results demonstrated significant increase and overexpression of EGFR in Bruneian lung cancer tissue samples in comparison to normal lung tissue. However, there was no significant relationship between clinicopathologic variables (age and sex) of patients and EGFR protein expression. Conclusions: EGFR is overexpressed in Bruneian lung cancer patient tissue samples in comparison to normal lung tissue samples. This may indicate that EGFR protein over expression plays an important role in the genesis of this type of cancer in Brunei Darussalam.

• Bulletin of the Korean Chemical Society
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• v.31 no.12
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• pp.3525-3529
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• 2010

Tyrosine kinase inhibitors (TKIs) are currently used in the treatment of patients with advanced lung cancer. Recent studies on non-small cell lung cancer have shown that some patients carry somatic mutations in the epidermal growth factor receptor (EGFR) gene. Such mutations correlate with the effectiveness of certain TKIs. To detect a small amount of mutant EGFR among an abundance of wild-type EGFR, we have developed a highly sensitive and simple method using PNA-mediated real-time PCR clamping. The PNA-mediated real-time PCR clamping enables detection of EGFR mutants down to approximately 1% mutant -to- wild type. The total assay time was short as it required only 2.0 hr. Thus, PNA-mediated real-time PCR clamping can easily be applied to clinical samples for identification of DNA carrying EGFR mutations and also appear to be the best assay to detect somatic mutations.

• Tuberculosis and Respiratory Diseases
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• v.54 no.1
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• pp.80-90
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• 2003

Background : Goblet cell hyperplasia is a critical pathological feature in hypersecretory diseases of the airways. A bacterial infection of the lung is also known to induce inflammatory responses, which can lead to the overproduction of mucus. Recently, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression and activation. In addition, it was reported that migration of the activated neutrophils is dependent on the matrix metalloproteinases (MMPs), especially MMP-9. In this study, bacterial lipopolysaccharide (LPS)-induced goblet cell hyperplasia and mucus hypersecretion by EGFR cascade, resulting from the MMPs-dependent neutrophilic inflammation were investigated in the rat airways. Methods : Pathogen-free Sprague-Dawley rats were studied in vivo. Various concentrations of LPS were instilled into the trachea in $300{\mu}{\ell}$ PBS (LPS group). Sterile PBS ($300{\mu}{\ell}$) was instilled into the trachea of the control animals (control group). The airways were examined on different days after instilling LPS. For an examination of the relationship between the LPS-induced goblet cell hyperplasia and MMPs, the animals were pretreated 3 days prior to the LPS instillation and daily thereafter with the matrix metalloproteinase inhibitor (MMPI; 20 mg/Kg/day of CMT-3; Collagenex Pharmaceuticals, USA). The neutrophilic infiltration was quantified as a number in five high power fields (HPF). The alcian blue/periodic acid-Schiff (AB/PAS) stain were performed for the mucus glycoconjugates and the immunohistochemical stains were performed for MUC5AC, EGFR and MMP-9. Their expressions were quantified by an image analysis program and were expressed by the percentage of the total bronchial epithelial area. Results : The instillation of LPS induced AB/PAS and MUC5AC staining in the airway epithelium in a time- and dose-dependent manner. Treatment with the MMPI prevented the LPS-induced goblet cell hyperplasia significantly. The instillation of LPS into the trachea induced also EGFR expression in the airway epithelium. The control airway epithelium contained few leukocytes, but the intratracheal instillation of LPS resulted in a neutrophilic recruitment. A pretreatment with MMPI prevented neutrophilic recruitment, EGFR expression, and goblet cell hyperplasia in the LPS-instilled airway epithelium. Conclusion : Matrix metalloproteinase is involved in LPS-induced mucus hypersecretion, resulting from a neutrophilic inflammation and EGFR cascade. These results suggest a potential therapeutic role of MMPI in the treatment of mucus hypersecretion that were associated with a bacterial infection of the airways.

• Tuberculosis and Respiratory Diseases
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• v.69 no.4
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• pp.271-278
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• 2010

Background: Recent studies have demonstrated that the epidermal growth factor receptor (EGFR) genotype is the most important predictive marker to EGFR-tyrosine kinase inhibitors (TKIs) and first-line gefitinib treatment will be approved in the near future for use in non-small cell lung cancer (NSCLC) patients with the EGFR mutation. Direct sequencing is known to be the standard for detecting EGFR mutations; however, it has limited sensitivity. Peptide nucleic acids (PNA)-mediated PCR clamping method is a newly introduced method for analyzing EGFR mutations with increased sensitivity and stability. Methods: A total of 71 NSCLC patients were analyzed for EGFR mutations using the PNA-mediated PCR clamping technique. Sixty-nine patients were analyzed for clinicopathologic correlation with EGFR genotype; 2 patients with indeterminate results were excluded. In order to determine EGFR-TKI drug response, 57 patients (42 gefitinib, 15 erlotinib) were included in the analysis. Results: The EGFR mutation rate was 47.8%. Being female, a non-smoker, and having adenocarcinoma were favorable clinicopathologic factors, as expected. However, more than a few smokers (33.3%), male (28.1%), and patients with non-adenocarcinoma (28.6%) had the EGFR mutation. Having a combination of favorable clinicopathologic factors did not increase the EGFR mutation rate significantly. Drug response to EGFR-TKIs showed significant differences depending on the EGFR genotype; ORR was 14.3% for wild type vs 69.0% for mutant type; DCR is 28.6% for wild type vs 96.6% for mutant type. The median EGFR-TKI treatment duration is 7.6 months for mutant type group and 1.4 months for wild type group. Conclusion: EGFR genotype determined using the PNA-mediated PCR clamping method is significantly correlated with the clinical EGFR-TKI responses and PNA-mediated PCR.

• Biomolecules & Therapeutics
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• v.24 no.2
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• pp.109-114
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• 2016

In Drosophila, rhomboid proteases are active cardinal regulators of epidermal growth factor receptor (EGFR) signaling pathway. iRhom1 and iRhom2, which are inactive homologs of rhomboid intramembrane serine proteases, are lacking essential catalytic residues. These are necessary for maturation and trafficking of tumor necrosis factor-alpha (TNF-${\alpha}$) converting enzyme (TACE) from endoplasmic reticulum (ER) to plasma membrane through Golgi, and associated with the fates of various ligands for EGFR. Recent studies have clarified that the activation or downregulation of EGFR signaling pathways by alteration of iRhoms are connected to several human diseases including tylosis with esophageal cancer (TOC) which is the autosomal dominant syndrom, breast cancer, and Alzheimer's disease. Thus, this review focuses on our understanding of iRhoms and the involved mechanisms in the cellular processes.

• Tuberculosis and Respiratory Diseases
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• v.81 no.2
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• pp.148-155
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• 2018

Background: Although targeted therapy and immuno-oncology have shifted the treatment paradigm for lung cancer, platinum-based combination is still the standard of care for advanced non-small cell lung cancer (NSCLC). Pemetrexed continuation maintenance therapy has been approved and increasingly used for patients with nonsquamous NSCLC. However, the efficacy of this strategy has not been proven in patients without driving mutations. The objective of this study was to compare the clinical benefit of pemetrexed continuation maintenance to conventional platinum-based doublet in epidermal growth factor receptor (EGFR)-negative lung adenocarcinoma. Methods: A total of 114 patients with EGFR-negative lung adenocarcinoma who were treated with platinum doublet were retrospectively enrolled. We compared the survival rates between patients received pemetrexed maintenance after four-cycled pemetrexed/cisplatin and those received at least four-cycled platinum doublet without maintenance chemotherapy as a first-line treatment. Results: Forty-one patients received pemetrexed maintenance and 73 received conventional platinum doublet. Median progression-free survival (PFS), which was defined as the time from the day of response evaluation after four cycles of chemotherapy to disease progression or death, was significantly higher in the pemetrexed maintenance group compared to conventional group (5.8 months vs. 2.2 months, p<0.001). Median overall survival showed an increasing trend in the pemetrexed maintenance group (22.3 months vs. 16.1 months, p=0.098). Multivariate analyses showed that pemetrexed maintenance chemotherapy was associated with better PFS (hazard ratio, 0.73; 95% confidence interval, 0.15-0.87). Conclusion: Compared to conventional platinum-based chemotherapy, premetrexed continuation maintenance treatment is associated with better clinical outcome for the patients with EGFR wild-type lung adenocarcinoma.

• Tuberculosis and Respiratory Diseases
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• v.80 no.2
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• pp.187-193
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• 2017

Background: Third-generation tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR-TKIs) have proved efficacious in treating non-small cell lung cancer (NSCLC) patients with acquired resistance resulting from the T790M mutation. However, since almost 50% patients with the acquired resistance do not harbor the T790M mutation, retreatment with first- or second-generation EGFR-TKIs may be a more viable therapeutic option. Here, we identified positive response predictors to retreatment, in patients who switched to a different EGFR-TKI, following initial treatment failure. Methods: This study retrospectively reviewed the medical records of 42 NSCLC patients with EGFR mutations, whose cancers had progressed following initial treatment with gefitinib or erlotinib, and who had switched to a different first-generation EGFR-TKI during subsequent retreatment. To identify high response rate predictors in the changed EGFR-TKI retreatment, we analyzed the relationship between clinical and demographic parameters, and positive clinical outcomes, following retreatment with EGFR-TKI. Results: Overall, 30 (71.4%) patients received gefitinib and 12 (28.6%) patients received erlotinib as their first EGFR-TKI treatment. Following retreatment with a different EGFR-TKI, the overall response and disease control rates were 21.4% and 64.3%, respectively. There was no significant association between their overall responses. The median progression-free survival (PFS) after retreatment was 2.0 months. However, PFS was significantly longer in patients whose time to progression was ${\geq}10months$ following initial EGFR-TKI treatment, who had a mutation of exon 19, or whose treatment interval was <90 days. Conclusion: In patients with acquired resistance to initial EGFR-TKI therapy, switched EGFR-TKI retreatment may be a salvage therapy for individuals possessing positive retreatment response predictors.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.1
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• pp.495-498
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• 2013

Epidermal growth factor receptor (EGFR) is over-expressed in several human cancers. This would suggest that inhibition of EGFR is a reasonable approach for cancer treatment. In this study we investigated EGFR blocking and its effects on the mediated signaling such as MAPK and STATb in HT29 cells. For this aim we used FITC-labeled EGFR antisense oligonucleotides encapsulated with PAMAM nanoparticles to inhibit EGFR expression. Cellular uptake of antisense was investigated by fluorescence microscopy and flow cytometry analysis. The effect of EGFR antisense on the expression of EGFR in HT29 cells was examined by real time PCR and Western blots, which showed that antisense encapsulated with PAMAM decreased the level of EGFR mRNA and protein. In addition, real time PCR results confirmed that EGFR inhibition had an effective role in the reduction of EGFR dependent downstream genes. In conclusion, EGFR antisense encapsulated with PAMAM nanoparticles down regulated EGFR and EGFR-mediated genes.