• Journal of Life Science
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• v.21 no.3
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• pp.349-357
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• 2011

Inhibitors of EGFR (epidermal growth factor receptor) kinase activity may prove useful to therapeutically intervene in cancer and to treat other proliferative diseases. In this study, we investigated the inhibitive effects of two compounds named 63013 and 63033 possess a [1,4]-dioxino quinazoline structure that links the alkoxy side chains together and their structural characteristics are considered to allow better solubility than the dialkoxyquinazoline derivatives. The EGFR kinase activities of A431 human epidermoid carcinoma cells, stimulated by EGF were inhibited by treatment with 63013 and 63033 in a dose-dependent manner respectively. Consistent with the compound-mediated EGFR kinase suppression, the major EGF-related downstream target molecules, such as MEK1/2, MAPK p44/42, AKT and STAT3, were also suppressed by both compounds. Interestingly, both compounds led to cell growth inhibition at a lower concentration than that of Gefitinib (Iressa$^{(R)}$). Collectively, our study showed that both compounds may have good therapeutic potential as an EGFR kinase specific inhibitor to treat EGFR-related diseases.

• Journal of the Korea Society of Computer and Information
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• v.21 no.9
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• pp.101-106
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• 2016

The epidermal growth factor receptor(EGFR) protein kinase signaling is an important pathway in cancer development and recently reported that EGFR and its kinase domain molecules are mutated in various of cancers including head and neck cancer. Functional deregulation of EGFR due to mutations in coding exons and copy number amplification is the most common event in cancers, especially among receptor tyrosine kinases(TK). We have analyzed Korean oral squamous cell carcinomas (OSCC) cell lines for mutations in EGFRTK. Exons encoding the hot-spot regions in the TK domain of EGFR (exons 17 to 23) were amplified by using polymerase chain reaction(PCR) and sequenced directly. EGFR expression was also analyzed in 8 OSCC cell lines using western blotting. Data analysis of the EGFR exons 17 to 23 coding sequences did not show any mutations in the 8 OSCC cell lines that were analyzed. The absence of mutations indicate that protein overexpression might be responsible for activation rather than mutation.

• Biomolecules & Therapeutics
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• v.30 no.1
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• pp.19-27
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• 2022

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wild-type EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second- and third-generation EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.35 no.5
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• pp.287-293
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• 2009

Cell survival is the result of a balance between programmed cell death and cellular proliferation. Cell membrane receptors and their associated signal transducing proteins control these processes. Of the numerous receptors and signaling proteins, epidermal growth factor receptor (EGFR) is one of the most important receptors involved in signaling pathways implicated in the proliferation and survival of cancer cells. EGFR is often highly expressed in human tumors including oral squamous cell carcinomas, and there is increasing evidence that high expression of EGFR is correlated with poor clinical outcome of common human cancers. Therefore, we examined the antiproliferative activity of gefitinib, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), in head and neck cancer cell lines. SCC-9, KB cells were cultured and growth inhibition activity of gefitinib was measured with MTT assay. To study influence of gefitinib in cell cycle, we performed cell cycle analysis with flow cytometry. Western blot was done to elucidate the expression of EGFR in cell lines and phosphorylation of EGFR and downstream kinase protein, Erk and Akt. Significant growth inhibition was observed in SCC-9 cells in contrast with KB cells. Also, flow cytometric analysis showed G1 phase arrest only in SCC-9 cells. In Western blot analysis for investigation of EGFR expression and downstream molecule phosphorylation, gefitinib suppressed phosphorylation of EGFR and downstream protein kinase Erk, Akt in SCC-9. However, in EGFR positive KB cells, weak expression of active form of Erk and Akt and no inhibitory activity of phosphorylation in Erk and Akt was observed. The antiproliferative activity of gefitinib was not correlated with EGFR expression and some possibility of phosphorylation of Erk and Akt as a predictive factor of gefitinib response was emerged. Further investigations on more reliable predictive factor indicating gefitinib response are awaited to be useful gefitinib treatment in head and neck cancer patients.

• Biomedical Science Letters
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• v.20 no.2
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• pp.85-95
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• 2014

Activation of the epidermal growth factor receptor (EGFR) and downstream signaling pathways have been implicated in causing resistance to EGFR-targeted therapy in solid tumors, including the head and neck tumors. To investigate the mechanism of antiproliferation to EGFR inhibition in oral cancer, we compared EGFR tyrosine kinase inhibitor (Gefitinib, Iressa, ZD1839) with respect to its inhibitory effects on three kinases situated downstream of EGFR: MAPK, Akt, and glycogen synthase kinase-$3{\beta}$ (GSK-$3{\beta}$). We have demonstrated that ZD1839 induces growth arrest and apotosis in oral cancer cell lines by independent of EGFR-mediated signaling. An exposure of oral cancer cells to ZD1839 resulted in a dose dependent up-regulation of the cyclin-dependent kinase inhibitor p21 and p27, down regulation of cyclin D1, inactivation of GSK-$3{\beta}$ and of active MAPK. In resistant cells, GSK-$3{\beta}$ is constitutively active and its activity is negatively regulated primarily through Ser 9 phosphorylation and further enhanced by Tyr216 phosphorylation. These results showed that the resistance to the antiproliferative effects of ZD1839, in vitro was associated with uncoupling between EGFR and MAPK inhibition, and that GSK-$3{\beta}$ activation and degradation of its target cyclin D1 were indicators of high cell sensitivity to ZD1839. In conclusion, our data show that the uncoupling of EGFR with mitogenic pathways can cause resistance to EGFR inhibition in oral cancer.

• Proceeding of EDISON Challenge
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• 2016.03a
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• pp.126-130
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• 2016

Epidermal growth factor receptor(EGFR)는 HER family에 속하는 tyrosine kinase receptor로서 다양한 하류경로로 신호를 전달하여 세포 증식, 혈관 형성, 세포 사멸을 억제하는 역할을 한다. EGFR이 폐암의 형성에 중요한 역할을 하고 많은 상피세포 종양에서 비정상적으로 활성화됨에 따라 암 치료에 중요한 역할을 하고 있어 EGFR tyrosine kinase inhibitor(TKI)에 관한 많은 연구가 이루어졌다. 위와 같은 약 개발에 있어서 현재 가상 시뮬레이션을 통한 약 후보물질 개발이 진행되고 있다. 특히, Molecular docking 시뮬레이션은 기존의 실험적인 기술(X-ray crystallography, NMR)로는 연구하기가 어려웠던 protein과 ligand간의 상호작용을 예측하여 이에 대한 정보를 제공할 수 있다. 하지만, 우선적으로 Molecular docking 시뮬레이션은 정확한 validation을 기반으로 진행되어야 신뢰할 수 있는 정보를 얻을 수 있다. 따라서 이번 연구에서는 EDISON에서 제공하는 Dock 프로그램과 일반적으로 잘 알려진 Glide, Autodock 프로그램으로 protein data bank(PDB)에서 제공하는 EGFR wild type cocrystal을 redocking하는 방식을 통하여 최상위 rank pose의 RMSD 값을 통한 validation 성능을 비교함으로써 어떤 프로그램이 EGFR과 ligand 간의 결합예측을 하는데 있어서 보다 더 정확한 결과를 낼 수 있는지 알아보고자 하였고 시뮬레이션 결과 Autodock에서 가장 우수한 결과 값을 보여주었다.

• BMB Reports
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• v.51 no.1
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• pp.27-32
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• 2018

Non-small-cell lung cancer (NSCLC) is commonly caused by a mutation in the epidermal growth factor receptor (EGFR) and subsequent aberrant EGFR signaling with uncontrolled kinase activity. A deletion mutation in EGFR exon 19 is frequently observed in EGFR gene mutations. We designed a DNAzyme to suppress the expression of mutant EGFR by cleaving the mutant EGFR mRNA. The DNAzyme (named Ex19del Dz) specifically cleaved target RNA and decreased cancer cell viability when transfected into gefitinib-resistant lung cancer cells harboring EGFR exon 19 deletions. The DNAzyme decreased EGFR expression and inhibited its downstream signaling pathway. In addition to EGFR downregulation, Ex19del Dz containing CpG sites activated Toll-like receptor 9 (TLR9) and its downstream signaling pathway via p38 kinase, causing an immunostimulatory effect on EGFR-mutated NSCLC cells. Thus, dual effects of this DNAzyme harboring the CpG site, such as TLR9 activation and EGFR downregulation, leads to apoptosis of EGFR-mutated NSCLC cells.

• Korean Journal of Clinical Pharmacy
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• v.18 no.2
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• pp.75-83
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• 2008

Purpose: Currently lung cancer ranks second in cancer for incidence rate and is a disease that ranks first for a death rate by cancerous growth because it is already advanced at the time of diagnosis. The purpose of this paper was to analyze the factors that affect the effectiveness of and rash occurrence by Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) in patients with non-small cell lung cancer. Methods: A retrospective chart review of 100 patients, who took EGFR TKI (erlotinib, gefitinib) among patients who were diagnosed with non-small cell lung cancer in a Hospital in Korea between May 2005 and February 2008, was conducted. The drug effectiveness was evaluated by Response Evaluation Criteria In Solid Tumor. Results: EGFR mutation was the only factor associated with drug response (complete response and partial response). When stable disease was added to drug response as the evaluation parameter, ECOG and rash as well as EGFR mutation were found to be important factors. Survival, however, was not affected by EGFR mutation. The factors influenced on survival were older age (${\geq}65$), low ECOG ($1{\sim}2$), adenocarcinoma and rash. In the case of rash, group with EGFR mutation or low ECOG showed significantly higher chance of occurrence. There was no significant difference in rash occurrence between gefitinib and erlotinib groups. Conclusions: Based on the results, EGFR mutation positive and low ECOG ($1{\sim}2$) were significantly important factors for both effectiveness of EGFR TKI and rash occurrence. Also, rash itself was found to be an independently significant factor for the disease control and survival. Therefore, while administering EGFR TKI, patients who have the factors associated with rash occurrence should be closely monitored for effective and safe drug therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.3187-3190
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• 2013

Background: Epidermal growth factor receptor (EGFR) is a transmembrane receptor which contributes to many processes involved in cell survival, proliferation and inhibits apoptosis, that may lead to cancer development. Gastric cancer is one of the most common diseases of digestive system that has low 5-year-survival. The aim of this research was to determine the significance of EGFR tyrosine kinase domain gene polymorphisms in gastric cancer in Iran. Materials and Methods: In the present study, 83 patients with gastric cancer and 40 normal subjects were investigated for EGFR gene polymorphisms in exons 18-21 by PCR-SSCP. Then, DNA sequencing was conducted for different mobility shift bands. Finally the data were statistically analyzed using the chi-2 test and the SPSSver.16 program. Results: Exon 18 of EGFR gene showed three different bands in SSCP pattern and DNA sequencing displayed one mutation. SSCP pattern of Exons 19 and 21 did not show different migration bands. Exon 20 of EGFR gene revealed multiple migrate bands in SSCP pattern. DNA sequencing displayed 2 mutations in this exon: one mutation was caused amino acid change and another mutation was silent. Conclusion: It may be that EGFR tyrosine kinase gene polymorphisms differ between populations and screening could be useful in gastric cancer patients who might benefit from tyrosine kinase inhibitor therapy.

• Tuberculosis and Respiratory Diseases
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• v.75 no.6
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• pp.236-237
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• 2013

Many attempts have been made to find genetic abnormalities inducing carcinogenesis after the development of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor targeting EGFR in lung cancer. New target therapies have been already commercialized and studied along with the recent discovery of gene rearrangement involved in the carcinogenic process of non-small cell lung cancer. This study aims to investigate anplastic lymphoma kinase, c-ros oncogene 1, and receptor tyrosine kinase, in particular.