EGFR-TKI获得性耐药相关T790M突变与非小细胞肺癌上皮间质转化和IGF-1R的相关性研究
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摘要
目的研究表皮生长因子受体-酪氨酸激酶抑制剂(EGFR-TKI)获得性耐药相关T790M突变与非小细胞肺癌上皮间质转化(EMT)和胰岛素样生长因子1型受体(IGF-1R)的相关性。方法选择我院2014年3月-2015年4月期间进行EGFR-TKI治疗并发生耐药的晚期非小细胞肺癌(NSCLC)患者64例,根据T790M突变情况分为突变组和未突变组,随访病情转归,检测肿瘤组织中EMT标志基因和IGF-1R通路分子的表达量。结果突变组患者无进展生存期及总生存期均显著短于未突变组(P<0.05);突变组肿瘤组织中波形蛋白(Vimentin)、N-钙黏蛋白(N-cadherin)、IGF-1R、磷脂酰肌醇3-激酶(PI3K)、蛋白激酶B(AKT)、细胞外信号调节激酶(ERK)的mRNA表达量显著高于未突变组,E-钙黏蛋白(E-cadherin)的mRNA表达量显著低于未突变组,差异均有统计学意义。结论 EGFR-TKI获得性耐药相关T790M突变可促进NSCLC肿瘤组织发生EMT和IGF-1R通路激活。
Objective To investigate the relationship of acquired resistance-related T790M mutation to epidermal growth factor receptortyrosine kinase inhibitor(EGFR-TKI) with the epithelial-mesenchymal transition(EMT) and insulin-like growth factor type 1 receptor(IGF-1R).Methods Sixty-four patients with advanced non-small cell lung cancer(NSCLC) who were treated with EGFR-TKI and acquired drug resistance in our hospital during March 2014 and April 2015 were selected. Then they were followed-up after divided into mutation group and non-mutation group according to T790M mutation. The expression of EMT marker genes and IGF-1R pathway molecules in the lesion were measured. Results The progression-free survival and total survival time of the mutation group were shorter than those of the non-mutation group. The mRNA expression levels of Vimentin, N-cadherin, IGF-1R, PI3K, AKT and ERK in lesions of mutation group were higher than those of the non-mutation group.The mRNA expression of E-cadherin in lesions of mutation group was lower than that of the non-mutation group. Conclusion Acquired resistancerelated T790M mutation to EGFR-TKI can aggravate the degree of EMT and the activation of IGF-1R pathway in tumor lesions.
Objective To investigate the relationship of acquired resistance-related T790M mutation to epidermal growth factor receptortyrosine kinase inhibitor(EGFR-TKI) with the epithelial-mesenchymal transition(EMT) and insulin-like growth factor type 1 receptor(IGF-1R).Methods Sixty-four patients with advanced non-small cell lung cancer(NSCLC) who were treated with EGFR-TKI and acquired drug resistance in our hospital during March 2014 and April 2015 were selected. Then they were followed-up after divided into mutation group and non-mutation group according to T790M mutation. The expression of EMT marker genes and IGF-1R pathway molecules in the lesion were measured. Results The progression-free survival and total survival time of the mutation group were shorter than those of the non-mutation group. The mRNA expression levels of Vimentin, N-cadherin, IGF-1R, PI3K, AKT and ERK in lesions of mutation group were higher than those of the non-mutation group.The mRNA expression of E-cadherin in lesions of mutation group was lower than that of the non-mutation group. Conclusion Acquired resistancerelated T790M mutation to EGFR-TKI can aggravate the degree of EMT and the activation of IGF-1R pathway in tumor lesions.
引文
[1]Abdallah SM, Hirsh V. Irreversible tyrosine kinase inhibition of epidermal growth factor receptor with afatinib in EGFR activating mutation-positive advanced non-small-cell lung cancer[J]. Curr Oncol, 2018, 25(Suppl 1):S9-S17. doi:10.3747/co.25.3732.
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[3]Wang Y, Wei Y, Ma X, et al. Association between advanced NSCLC T790 M EGFR-TKI secondary resistance and prognosis:A observational study[J]. Medicine(Baltimore), 2018,97(28):e11346. doi:10.1097/MD.0000000000011346.
[4]Nie K, Jiang H, Zhang C, et al. Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients[J]. Biomed Res Int,.2018, 2018:9010353. doi:10.1155/2018/9010353.
[5]吴鹏飞,朱益平,杨春晖,等.表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)继发性耐药的机制及对策[J].肿瘤药学,2015, 5(4):246-250. doi:10.3969/j. issn.2095-1264.2015.04.02.
[6]Nishikawa S, Kimura H, Koba H, et al. Selective gene amplification to detect the T790M mutation in plasma from patients with advanced non-small cell lung cancer(NSCLC)who have developed epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)resistance[J]. J Thorac Dis, 2018, 10(3):1431-1439. doi:10.21037/jtd.2018.01.144.
[7]Li C, Jia R, Liu H, et al. EGFR T790M detection and osimertinib treatment response evaluation by liquid biopsy in lung adenocarcinoma patients with acquired resistance to first generation EGFR tyrosine kinase inhibitors[J]. Diagn Pathol, 2018, 13(1):49. doi:10.1186/s13000-018-0728-6.
[8]魏媛,魏莉,马晓平,等. T790M与晚期NSCLC患者EGFR-TKI继发耐药及预后的相关性[J].中华肿瘤防治杂志, 2016, 23(6):364-368. doi:10.16073/j. cnki.cjcpt.2016.06.004.
[9]王津京,张为民,陈蓓,等.上皮间质转化和胰岛素样生长因子I型受体在非小细胞肺癌EGFR-TKIs获得性耐药中的作用[J].肿瘤, 2013, 33(2):103-110. DOI:10.3781/j. issn.1000-7431.2013.02.001.
[10]Milano A, Mazzetta F, Valente S, et al. Molecular Detection of EMT Markers in Circulating Tumor Cells from Metastatic Non-Small Cell Lung Cancer Patients:Potential Role in Clinical Practice[J]. Anal Cell Pathol(Amst), 2018, 2018:3506874. doi:10.1155/2018/3506874.
[11]Luo T, Wang L, Wu P, et al. Downregulated vimentin and upregulated E-cadherin in T1 stage non-small-cell lung cancer:does it suggest a mesenchymal-epithelial transition?[J]. Neoplasma, 2017, 64(5):693-699. doi:10.4149/neo_2017_506.
[12]Quintanal-Villalongaá, Ojeda-Márquez L, Marrugalá,et al. The FGFR4-388arg Variant Promotes Lung Cancer Progression by N-Cadherin Induction[J]. Sci Rep, 2018,8(1):2394. doi:10.1038/s41598-018-20570-3.
[13]张曦,黄选章,曾云云,等.靶向抑制IGF-1R逆转非小细胞肺癌对EGFR-TKIs获得性耐药的研究[J].浙江实用医学, 2018, 23(3):157-161. doi:10.16794/j. cnki.cn33-1207/r.2018.03.001.
[14]Zhao J, Shi X, Wang T, et al. The Prognostic and Clinicopathological Significance of IGF-1R in NSCLC:a MetaAnalysis[J]. Cell Physiol Biochem, 2017, 43(2):697-704.doi:10.1159/000480655.
[15]Yeo CD, Kim YA, Lee HY, et al. Inhibiting IGF-1R attenuates cell proliferation and VEGF production in IGF-1R over-expressing EGFR mutant non-small cell lung cancer cells[J]. Exp Lung Res, 2017, 43(1):29-37. doi:10.1080/01902148.2017.1282994.
[2]Peng M, Weng YM, Liu HL, et al. Clinical Characteristics and Survival Outcomes for Non-Small-Cell Lung Cancer Patients with Epidermal Growth Factor Receptor Double Mutations[J]. Biomed Res Int, 2018, 2018:7181368. doi:10.1155/2018/7181368.
[3]Wang Y, Wei Y, Ma X, et al. Association between advanced NSCLC T790 M EGFR-TKI secondary resistance and prognosis:A observational study[J]. Medicine(Baltimore), 2018,97(28):e11346. doi:10.1097/MD.0000000000011346.
[4]Nie K, Jiang H, Zhang C, et al. Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients[J]. Biomed Res Int,.2018, 2018:9010353. doi:10.1155/2018/9010353.
[5]吴鹏飞,朱益平,杨春晖,等.表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)继发性耐药的机制及对策[J].肿瘤药学,2015, 5(4):246-250. doi:10.3969/j. issn.2095-1264.2015.04.02.
[6]Nishikawa S, Kimura H, Koba H, et al. Selective gene amplification to detect the T790M mutation in plasma from patients with advanced non-small cell lung cancer(NSCLC)who have developed epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)resistance[J]. J Thorac Dis, 2018, 10(3):1431-1439. doi:10.21037/jtd.2018.01.144.
[7]Li C, Jia R, Liu H, et al. EGFR T790M detection and osimertinib treatment response evaluation by liquid biopsy in lung adenocarcinoma patients with acquired resistance to first generation EGFR tyrosine kinase inhibitors[J]. Diagn Pathol, 2018, 13(1):49. doi:10.1186/s13000-018-0728-6.
[8]魏媛,魏莉,马晓平,等. T790M与晚期NSCLC患者EGFR-TKI继发耐药及预后的相关性[J].中华肿瘤防治杂志, 2016, 23(6):364-368. doi:10.16073/j. cnki.cjcpt.2016.06.004.
[9]王津京,张为民,陈蓓,等.上皮间质转化和胰岛素样生长因子I型受体在非小细胞肺癌EGFR-TKIs获得性耐药中的作用[J].肿瘤, 2013, 33(2):103-110. DOI:10.3781/j. issn.1000-7431.2013.02.001.
[10]Milano A, Mazzetta F, Valente S, et al. Molecular Detection of EMT Markers in Circulating Tumor Cells from Metastatic Non-Small Cell Lung Cancer Patients:Potential Role in Clinical Practice[J]. Anal Cell Pathol(Amst), 2018, 2018:3506874. doi:10.1155/2018/3506874.
[11]Luo T, Wang L, Wu P, et al. Downregulated vimentin and upregulated E-cadherin in T1 stage non-small-cell lung cancer:does it suggest a mesenchymal-epithelial transition?[J]. Neoplasma, 2017, 64(5):693-699. doi:10.4149/neo_2017_506.
[12]Quintanal-Villalongaá, Ojeda-Márquez L, Marrugalá,et al. The FGFR4-388arg Variant Promotes Lung Cancer Progression by N-Cadherin Induction[J]. Sci Rep, 2018,8(1):2394. doi:10.1038/s41598-018-20570-3.
[13]张曦,黄选章,曾云云,等.靶向抑制IGF-1R逆转非小细胞肺癌对EGFR-TKIs获得性耐药的研究[J].浙江实用医学, 2018, 23(3):157-161. doi:10.16794/j. cnki.cn33-1207/r.2018.03.001.
[14]Zhao J, Shi X, Wang T, et al. The Prognostic and Clinicopathological Significance of IGF-1R in NSCLC:a MetaAnalysis[J]. Cell Physiol Biochem, 2017, 43(2):697-704.doi:10.1159/000480655.
[15]Yeo CD, Kim YA, Lee HY, et al. Inhibiting IGF-1R attenuates cell proliferation and VEGF production in IGF-1R over-expressing EGFR mutant non-small cell lung cancer cells[J]. Exp Lung Res, 2017, 43(1):29-37. doi:10.1080/01902148.2017.1282994.