The research on the change of chemosensitivity of gefitinib-resistant lung adenocarcinoma cell caused by EGFR-T790M mutation

李学真; 邹文; 马进安

doi:10.3969/j.issn.1007-3969.2015.02.008

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The research on the change of chemosensitivity of gefitinib-resistant lung adenocarcinoma cell caused by EGFR-T790M mutation

更新时间：2025-12-31

- The research on the change of chemosensitivity of gefitinib-resistant lung adenocarcinoma cell caused by EGFR-T790M mutation
- China Oncology Vol. 25, Issue 2, Pages: 129-134(2015)
- 作者机构：
  
  中南大学湘雅二医院肿瘤科,湖南,长沙,410011
- 作者简介：
- 基金信息：
- DOI：10.3969/j.issn.1007-3969.2015.02.008
  CLC：
- Published Online：13 May 2015，
  
  Published：13 May 2015
- 稿件说明：
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李学真,邹文,马进安,等. EGFR-T790M突变所致吉非替尼耐药肺腺癌细胞化疗药物敏感性变化的研究[J]. 中国癌症杂志, 2015, 25(2): 129-134.

李学真, 邹文, 马进安. The research on the change of chemosensitivity of gefitinib-resistant lung adenocarcinoma cell caused by EGFR-T790M mutation[J]. China Oncology, 2015, 25(2): 129-134.
李学真,邹文,马进安,等. EGFR-T790M突变所致吉非替尼耐药肺腺癌细胞化疗药物敏感性变化的研究[J]. 中国癌症杂志, 2015, 25(2): 129-134. DOI： 10.3969/j.issn.1007-3969.2015.02.008.

李学真, 邹文, 马进安. The research on the change of chemosensitivity of gefitinib-resistant lung adenocarcinoma cell caused by EGFR-T790M mutation[J]. China Oncology, 2015, 25(2): 129-134. DOI： 10.3969/j.issn.1007-3969.2015.02.008.

摘要

背景与目的：EGFR-TKI治疗NSCLC失败后，化疗仍可取得一定的治疗效果，是可选择的治疗方案之一。核苷酸还原酶(ribonucleotide reductase，RR)、胸苷酸合成酶(thymidylate synthase，TS)、核苷酸切除修复交叉互补基因1(excision repair cross complementstion group 1，ERCC1)、3型β微管蛋白(β-tubulin-Ⅲ，TUBB3)分别与吉西他滨、培美曲塞、铂类药物及微管类药物的化疗药物敏感性存在相关性，可以通过这些分子标志物的表达水平来预测化疗药物的敏感性。RRMI、TS、ERCC1和TUBB3高表达患者化疗药物的敏感性降低，低表达患者化疗药物敏感性增高。本研究拟探讨EGFR-T790M突变所致吉非替尼耐药肺腺癌细胞对顺铂、吉西他滨、长春瑞滨、紫杉醇、多西他赛和培美曲塞化疗药物敏感性的变化。方法：通过MTT法检测PC9及PC9/GR细胞对顺铂、吉西他滨、长春瑞滨、紫杉醇、多西他赛和培美曲塞的IC50，探讨其对上述药物的化疗敏感性。采用液相芯片法，检测PC9及PC9/GR细胞ERCC1 mRNA、RRM1 mRNA、TUBB3 mRNA和TS mRNA的表达水平。通过蛋白质印迹法(Western blot)检测PC9及PC9/GR细胞ERCC1、RRM1、TUBB3和TS蛋白的表达水平。结果：与PC9细胞株相比较，PC9/GR细胞株对吉非替尼、顺铂、吉西他滨和培美曲塞的IC50明显增高(P＜0.05)；对长春瑞滨、紫杉醇和多西他赛的IC50明显降低(P＜0.05)。PC9/GR细胞对吉非替尼、顺铂、吉西他滨、长春瑞滨、紫杉醇、多西他赛和培美曲塞的耐药指数分别为70、1.56、1.61、0.34、0.39、0.14和1.71。与PC9细胞株mRNA的表达量相比较，PC9/GR细胞株ERCC1 mRNA、RRM1 mRNA和TS mRNA的表达量明显增高(P＜0.05)，TUBB3的mRNA的表达量明显降低，差异均有统计学意义(P＜0.05)。与PC9细胞株蛋白的表达量相比较，PC9/GR细胞株ERCC1、RRM1和TS的蛋白表达量明显增高，TUBB3蛋白的表达量明显降低，差异均有统计学意义(P＜0.05)。结论：肺腺癌细胞株发生EGFR-T790M突变后对化疗药物敏感性发生变化，对顺铂、吉西他滨和培美曲塞的敏感性降低，对长春瑞滨、紫杉醇和多西他赛的敏感性增高；其化疗药物敏感性发生变化的原因可能与肺腺癌细胞株发生EGFR-T790M突变后ERCC1 mRNA、RRM1 mRNA、TS mRNA及其蛋白表达量发生变化相关。

Abstract

Background and purpose: Chemotherapy is an alternative treatment option

which could still get a therapeutic effect

when the EGFR-TKI treatment of non-small cell lung cancer failed. Studies have shown that RR

TYMS

ERCC1 and TUBB3 have respectively relationship with chemosensitivity of gemcitabine

pemetrexed

platinum-based drugs and microtubule-based chemotherapy drugs.The expression levels of these molecular markers can predict the sensitivity of these chemotherapy drugs. The patients with RRMI

ERCC1 and TUBB3 higher expression have reduced chemosensitivity

and lower expression have increased sensitivity. The purpose of this study was to explore the sensitivity of tumor cell lines with acquired resistance to gefitinib caused by EGFR-T790M mutation to cisplatin

gemcitabine

pemetrexed

vinorelbine

paclitaxel and docetaxel. Methods: MTT assay was used to detect the IC50 values of cisplatin

gemcitabine

vinorelbine

paclitaxel and docetaxel

pemetrexed to PC9 and PC9/GR cells

and to explore the chemosensitivity of lung adenocarcinoma cells to these chemotherapy drugs; Luminex method was used respectively to detect the expression levels of ERCC1 mRNA

TUBB3 mRNA

TS mRNA

and RRM1 mRNA in PC9 and PC9/GR cells. Western blot was used to detect the protein expression levels of ERCC1

TUBB3

TS and RRM1 in PC9 and PC9/GR cells. Results: The IC50 values of cisplatin

gemcitabine and pemetrexed to PC9/GR cells were significantly higher than those to PC9 cells (P0.05)

while the IC50 values of vinorelbine

paclitaxe and docetaxel to PC9/GR cells were significantly decreased (P0.05). Luminex method showed the expressions of ERCC1 mRNA

TS mRNA and RRM1 mRNA in PC9/GR cells were significantly increased than those in PC9 cells (P0.05)

while the expression of TUBB3 mRNA was significantly decreased (P0.05). Western blot method showed the expressions of TUBB3

TS and RRM1 protein in PC9/GR cells were significantly increased than those in PC9 cells (P0.05)

while TUBB3 protein expression in PC9/GR cells was significantly decreased (P0.05). Western blot method analysis result showed that the expressions of TUBB3

TS and RRM1 protein in PC9/GR cells were significantly increased than those in PC9 cells (P0.05)

while TUBB3 protein expression in PC9/GR cells was significantly decreased (P0.05). Conclusion: The chemosensitivity of lung adenocarcinoma with EGFR-T790M mutation is changed. It has decreased sensitivity to cisplatin

gemcitabine

pemetrexed and increased sensitivity to vinorelbine

paclitaxel and docetaxel. The reason of the change of chemosensitivity of gefitinib-resistant lung adenocarcinoma cell maybe related to the changes of ERCC1 mRNA

RRM1 mRNA and TS mRNA and their protein expressions.

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