Dataset Information

Concurrent epidermal growth factor receptor T790M secondary mutation and epithelial-mesenchymal transition in a lung adenocarcinoma patient with EGFR-TKI drug resistance.

ABSTRACT: Almost all epidermal growth factor receptor (EGFR)-mutant lung cancers develop resistance to EGFR-tyrosine kinase inhibitors. Several mechanisms for this acquired resistance have been identified, including development of an EGFR T790M mutation, MET amplification, hepatocyte growth factor overexpression, loss of phosphatase and tensin homolog expression, epithelial-mesenchymal transition, and transformation to small cell lung cancer. Herein, we report a case of a lung cancer patient with EGFR exon 19 deletion who was resistant to EGFR-tyrosine kinase inhibitor treatment during disease progression. Using histological and gene sequencing analysis, we observed that the primary adenocarcinoma acquired T790M mutation in EGFR exon 20, and a secondary sarcomatoid carcinoma developed in the vicinity. Assessment of E-cadherin and Vimentin expression confirmed that the sarcomatoid carcinoma had undergone an epithelial-mesenchymal transition. Therefore, it is important to perform a tissue re-biopsy after the development of resistance to identify the best treatment options. Surgical resection might be a better "salvage" treatment in cases of oligometastatic progression.

SUBMITTER: Xu S

PROVIDER: S-EPMC5668506 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Concurrent epidermal growth factor receptor T790M secondary mutation and epithelial-mesenchymal transition in a lung adenocarcinoma patient with EGFR-TKI drug resistance.

Xu Song S Liu Xia X Liu Renwang R Shi Tao T Li Xiongfei X Zhong Diansheng D Wang Yan Y Chen Gang G Chen Jun J

Thoracic cancer 20170808 6

Almost all epidermal growth factor receptor (EGFR)-mutant lung cancers develop resistance to EGFR-tyrosine kinase inhibitors. Several mechanisms for this acquired resistance have been identified, including development of an EGFR T790M mutation, MET amplification, hepatocyte growth factor overexpression, loss of phosphatase and tensin homolog expression, epithelial-mesenchymal transition, and transformation to small cell lung cancer. Herein, we report a case of a lung cancer patient with EGFR exo ...[more]

PMID: 28786540

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Project description:In Taiwan, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), gefitinib, erlotinib, and afatinib are served as first-line therapy for non-small lung cell cancer (NSCLC) patients with EGFR sensitizing mutations. However, the majority of patients who initially respond to EGFR-TKIs, progress through acquiring EGFR T790M mutations (T790M), which is the most common resistant mechanism. Patients with T790M gain the opportunity of subsequent treatment with third-generation EGFR-TKI, osimertinib. This study aimed to evaluate the association between prior EGFR-TKI therapy and incidence of acquired T790M resistance in lung adenocarcinoma patients who have progressed on first/second-generation EGFR-TKI therapy. This retrospective study included lung adenocarcinoma patients who had a radiographically-confirmed progressive disease under EGFR-TKI treatment and had re-biopsy samples for T790M testing from seven medical centers in Taiwan from June 2013 to December 2018. Patients harboring de novo T790M or using more than one EGFR-TKI were excluded. Of the 407 patients enrolled, the overall T790M acquisition rate was 52.8%. The patients treated with gefitinib, erlotinib or afatinib had a statistically significant difference in the T790M rates (59.9, 45.5, and 52.7%, respectively; p = 0.037) after disease progression. Patients with common baseline EGFR mutations (Del-19 and L858R) (p = 0.005) and longer treatment duration with EGFR-TKIs (p < 0.001) had higher chances of T790M acquisition. Multivariate logistic regression analysis further showed that patients with common baseline EGFR mutations, gefitinib (compared to erlotinib) administration, and longer treatment duration with EGFR-TKIs had higher T790M incidence. There was no significant difference in the incidence of acquired T790M between different re-biopsy tissue samples or complications. In conclusion, this study showed that patients who progressed from gefitinib treatment, bearing common EGFR mutations, and with longer EGFR-TKI treatment duration had increased incidence of T790M acquisition and, therefore, were suitable for subsequent osimertinib treatment.

Project description:BackgroundLung cancer is the most common and lethal malignancy worldwide. TCTP is highly expressed in various cancers including lung cancer. Epithelial-mesenchymal transition (EMT) could increase cancer cell invasion. Whether TCTP's expression is associated with EMT in lung adenocarcinoma is largely unknown.MethodsSeveral Gene Expression Omnibus datasets were used to analyze the correlation between TCTP expression and overall survival of lung adenocarcinoma patients by Kaplan-Meier survival analysis. Then, 24 surgically removed fresh lung adenocarcinoma tissue samples and paired paracancer tissue samples were used to analyze the correlation between TCTP expression and tumor stage by immunohistochemical analysis. Furthermore, stable cell lines were generated using lentiviral transduction systems to knock down or overexpress TCTP in A549 cells. Cell migration and invasion were measured by scratch and transwell assays, and EMT marker proteins such as α-SMA, ZEB1, and E-cadherin were quantitated by Western blot. The expression levels of miR-200a, miR-141, and miR-429 were determined by real-time quantitative PCR, and their target genes were predicted by an online database miRTarBase. The interaction between TCTP and these genes was analyzed by String database and visualized by Cytoscape.ResultsTCTP was highly expressed in tumor tissues compared to paracancer tissues. The expression of TCTP was associated with shorter overall survival. TCTP knockdown experiment in A549 cells suggested that TCTP knockdown could decrease the migration and invasion of lung cancer cells, and the expression level of ZEB1 and α-SMA, but increase the expression of E-cadherin and p53. Vice versa, overexpression of TCTP could increase the migration and invasion of cancer cells, and the expression level of ZEB1 and α-SMA, but decrease the expression of E-cadherin and p53. Furthermore, we found the expression of miR-200a, miR-141, and miR-429 was associated with TCTP expression.ConclusionTCTP promotes EMT in lung adenocarcinoma, and this effect may be associated with miR-200 family members like miR-200a, miR-141, and miR-429.

Dataset Information

Concurrent epidermal growth factor receptor T790M secondary mutation and epithelial-mesenchymal transition in a lung adenocarcinoma patient with EGFR-TKI drug resistance.

Publications

Concurrent epidermal growth factor receptor T790M secondary mutation and epithelial-mesenchymal transition in a lung adenocarcinoma patient with EGFR-TKI drug resistance.

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