• Korean Journal of Head & Neck Oncology
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• v.35 no.2
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• pp.19-25
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• 2019

Background/Objectives: Although anaplastic thyroid carcinoma (ATC) is rare, it is one of the deadliest forms of thyroid cancer. The fatality rate for ATC is high, and the survival rate at one year after diagnosis is <20%. The present study aimed to investigate the anti-tumor activities of paclitaxel, radiation, and tyrosine kinase inhibitor (TKI) combined therapy in anaplastic thyroid cancer cells both in vitro and in vivo and explore its effects on apoptotic cell death pathways. Materials & Methods: ATC cell line was exposed to TKI, lenvatinib in the presence or absence of paclitaxel with radiation, and cell viability was determined by MTT assay. Effects of the combined treatment on cell cycle and intracellular signaling pathways were assessed by flow cytometry and western blot analysis. The ATC cell line xenograft model was used to examine the anti-tumor activity in vivo. Results: Our data revealed that the combined administration of paclitaxel, TKI, and radiation decreased cell viability in ATC cells, and also significantly increased apoptotic cell death in these cells, as demonstrated by the cleavage of caspase-3 and DNA fragmentation. This combination therapy reduced anti-apoptotic factor levels in ATC cells, while significantly decreasing tumor volume and increasing survival in ATC xenografts. Conclusion: These results indicate that administering the combination of paclitaxel, TKI, and radiation therapy may exert significant anticancer effects in preclinical models, potentially suggesting a new clinical approach for treating patients with ATC.

• Molecules and Cells
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• v.39 no.5
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• pp.389-394
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• 2016

Dovitinib (TKI258) is a small molecule multi-kinase inhibitor currently in clinical phase I/II/III development for the treatment of various types of cancers. This drug has a safe and effective pharmacokinetic/pharmacodynamic profile. Although dovitinib can bind several kinases at nanomolar concentrations, there are no reports relating to osteoporosis or osteoblast differentiation. Herein, we investigated the effect of dovitinib on human recombinant bone morphogenetic protein (BMP)-2-induced osteoblast differentiation in a cell culture model. Dovitinib enhanced the BMP-2-induced alkaline phosphatase (ALP) induction, which is a representative marker of osteoblast differentiation. Dovitinib also stimulated the translocation of phosphorylated Smad1/5/8 into the nucleus and phosphorylation of mitogen-activated protein kinases, including ERK1/2 and p38. In addition, the mRNA expression of BMP-4, BMP-7, ALP, and OCN increased with dovitinib treatment. Our results suggest that dovitinib has a potent stimulating effect on BMP-2-induced osteoblast differentiation and this existing drug has potential for repositioning in the treatment of bone-related disorders.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.7
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• pp.3025-3033
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• 2016

Chronic myeloid leukaemia (CML) is a clonal myeloproliferative hematopoietic stem cell disorder. Deregulated BCR-ABL fusion tyrosine kinase activity is the main cause of CML disease pathogenesis, making BCR-ABL an ideal target for inhibition. Current tyrosine kinase inhibitors (TKIs) designed to inhibit BCR-ABL oncoprotein activity, have completely transformed the prognosis of CML. Interruption of TKI treatment leads to minimal residual disease reside (MRD), thought to reside in TKI-insensitive leukaemia stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML either as small molecule master TKIs or phytopharmaceuticals derived from nature to achieve chronic molecular remission. This review outlines the past, present and future therapeutic approaches for CML including coverage of relevant mechanisms, whether ABL dependent or independent, and epigenetic factors responsible for developing resistance against TKIs. Appearance of mutant clones along the course of therapy either pre-existing or induced due to therapy is still a challenge for the clinician. A proposed in-vitro model of generating colony forming units from CML stem cells derived from diagnostic samples seems to be achievable in the era of high throughput technology which can take care of single cell genomic profiling.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.2
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• pp.695-700
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• 2013

Background: Mutations affecting the epidermal growth factor receptor (EGFR) are good predictors of clinical efficacy of EGFR tyrosine kinase inhibitors (TKI) in patients with non-small cell lung cancer. Serum carcinoembryonic antigen (CEA) levels are also regarded as predictive for the efficacy of EGFR-TKI and EGFR gene mutations. This study analyzed the association between EGFR gene mutations and clinical features, including serum tumor marker levels in lung adenocarcinomas patients. Patients and Methods: A total of 70 lung adenocarcinoma patients with complete clinical data and pathological specimens were investigated. EGFR gene mutations at exons 19 and 21 were assessed. Serum tumor markers were detected by protein chip-chemiluminescence at the corresponding time, and correlations were analyzed. Results: Mutations of the EGFR gene were detected in 27 of the 70 patients and the serum CEA and CA242 concentrations were found to be significantly associated with the incidence of EGFR gene mutations (P<0.05). The AUCs for CEA and CA242 were 0.724 (95% CI: 0.598~0.850, P<0.05) and 0.769 (95% CI: 0.523~0.800, P<0.05) respectively. Conclusions: Serum CEA and CA242 levels are associated with mutations of the EGFR gene in patients with lung adenocarcinomas.

• 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.

• Tuberculosis and Respiratory Diseases
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• v.78 no.4
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• pp.315-320
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• 2015

Background: The efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy can be measured based on the rate of treatment response, based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria or progression-free survival (PFS). However, there are some patients harboring sensitive EGFR mutations who responded poorly to EGFR-TKI therapy. In addition, there is variability in the PFS after EGFR-TKI treatment. Methods: We performed a retrospective analysis of the medical records of 85 patients with non-small cell lung cancer, who had achieved a stable disease or better response at the first evaluation of treatment response, after receiving a 2-month course of gefitinib. We calculated the tumor shrinkage rate (TSR) by measuring the longest and perpendicular diameter of the main mass on computed tomography before, and 2 months after, gefitinib therapy. Results: There was a significant positive correlation between the TSR and PFS (R=0.373, p=0.010). In addition, a simple linear regression analysis showed that the TSR might be an indicator for the PFS ($B{\pm}standard$ error, $244.54{\pm}66.79$; p=0.001). On univariate analysis, the sex, histologic type, smoking history and the number of prior chemotherapy regimens, were significant prognostic factors. On multivariate regression analysis, both the TSR (${\beta}$=0.257, p=0.029) and adenocarcinoma (${\beta}$=0.323, p=0.005) were independent prognostic factors for PFS. Conclusion: Our results showed that the TSR might be an early prognostic indicator for PFS in patients receiving EGFRTKI therapy.

• Journal of Digestive Cancer Research
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• v.3 no.1
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• pp.11-16
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• 2015

The discovery of HER2, a biomarker in advanced gastric cancer, and successful clinical trial using trastuzumab that targets this biomarker signaled a revolutionary turning point in treatment of metastatic gastric cancer. Many studies about targeted agents for gastric cancer have been attempted. Among them, ramicirumab, a monoclonal antibody that targets vascular endothelial growth factor receptor-2 (VEGFR-2), and apatinib, a tyrosine kinase inhibitor (TKI) that targets VEGFR2, have shown to improve the survival rates in advanced gastric cancer patients, for whom previous therapies had failed; hence, they are expected to be accepted as one of the standard therapies for advanced gastric cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.11
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• pp.4493-4497
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• 2014

Background: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) can predict the clinical response to tyrosine kinase inhibitor (TKI) therapy. However, EGFR mutations may be different in primary tumors (PT) and metastatic lymph nodes (MLN). The aim of this study was to compare EGFR mutations between PT and the corresponding MLN in NSCLC patients, and provide some guidelines for clinical treatment using TKI therapy. Materials and Methods: A systematic review and meta-analysis was performed with several research databases. Relative risk (RR) with the 95% confidence interval (CI) were used to investigate the EGFR mutation status between PT and the corresponding MLN. A random-effects model was used. Results: 9 publications involving 707 patients were included in the analysis. It was found that activation of EGFR mutations identified in PT and the corresponding MLN was 26.4% (187/707) and 19.9% (141/707), respectively. The overall discordance rate in our meta-analysis was 12.2% (86/707). The relative risk (RR) for EGFR mutation in PT relative to MLN was 1.33 (95%CI: 1.10-1.60; random-effects model). There was no significant heterogeneity between the studies ($I^2$=5%, p=0.003). Conclusions: There exists a considerable degree of EGFR mutation discrepancy in NSCLC between PT and corresponding MLN, suggesting that tumor heterogeneity might arise at the molecular level during the process of metastasis.

• Tuberculosis and Respiratory Diseases
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• v.83 no.1
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• pp.51-60
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• 2020

Background: Programmed death-ligand 1 (PD-L1) expression is tested by immunohistochemistry (IHC)-22C3, SP263, and SP142. The aim of this study is to evaluate the correlation among the three methods of PD-L1 IHC in non-small cell lung cancer (NSCLC) and clinical significance of PD-L1 expression in lung adenocarcinoma with an epidermal growth factor receptor (EGFR)-tyrosine kinase domain mutation. Methods: The results of 230 patients who were pathologically confirmed as having NSCLC; tested using PD-L1 IHC 22C3, SP263, and SP142 methods; and evaluated via the peptide nucleic acid clamping method to confirm EGFR mutation, were analyzed in this study. Results: 164 patients underwent both the SP263 and 22C3 tests. There was a significant positive correlation between the outcomes of the two tests (Spearman correlation coefficient=0.912, p<0.001), with a derived regression equation as follows: 22C3=15.2+0.884×SP263 (R²=0.792, p<0.001). There was no relationship between the expression of PD-L1 and clinical parameters, including EGFR-tyrosine kinase inhibitor (TKI) mutation. The PD-L1 expression in patients treated with EGFR-TKI yielded a 2-month-shorter progression period than that in the PD-L1-negative group. However, this did not reach statistical significance (PD-L1<1% vs. PD-L1≥1%, 10 months vs. 8 months). Conclusion: The results of the 22C3 and those of SP263 methods were in good correlation with one another. Since the PD-L1 expression is not influenced by the EGFR mutation, it is necessary to perform a PD-L1 test to set the treatment direction in the patients with EGFR-mutant NSCLC.

• 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.