电离辐射降低NSCLC细胞株T790M突变所致TKI耐药
背景与目的以表皮生长因子受体(epidermal growth factor receptor,EGFR)为靶点的分子靶向治疗在非小细胞肺癌(non-small cell lung cancer,NSCLC)的治疗中发挥重要的作用。EGFR突变的患者对EGFR酪氨酸激酶抑制剂(EGFR-tyrosine kinase inhibitor,EGFR-TKI)治疗敏感、疗效显著,但无论近期疗效如何,患者最终都不可避免地产生耐药。大量研究证实,EGFR基因的二次突变(T790M)是患者耐药的主要原因。本研究旨在探讨电离辐射对NSCLC细胞株T790M突变所致EGFR-TKI耐药的影响。方法选择NSC...
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| Published in | 中国肺癌杂志 no. 8; pp. 475 - 480 |
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| Main Author | |
| Format | Journal Article |
| Language | Chinese |
| Published |
南京大学医学临床学院南京军区南京总医院, 南京,210002
2015
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| Subjects | |
| Online Access | Get full text |
| ISSN | 1009-3419 1999-6187 |
| DOI | 10.3779/j.issn.1009-3419.2015.08.02 |
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| Abstract | 背景与目的以表皮生长因子受体(epidermal growth factor receptor,EGFR)为靶点的分子靶向治疗在非小细胞肺癌(non-small cell lung cancer,NSCLC)的治疗中发挥重要的作用。EGFR突变的患者对EGFR酪氨酸激酶抑制剂(EGFR-tyrosine kinase inhibitor,EGFR-TKI)治疗敏感、疗效显著,但无论近期疗效如何,患者最终都不可避免地产生耐药。大量研究证实,EGFR基因的二次突变(T790M)是患者耐药的主要原因。本研究旨在探讨电离辐射对NSCLC细胞株T790M突变所致EGFR-TKI耐药的影响。方法选择NSCLC细胞株H1975和H3255为研究对象,实时荧光定量PCR法检测两株细胞的突变状态、克隆形成实验观察两株细胞的放射敏感性,MTT法检测各处理组两株细胞对EGFR-TKI的抗药性。结果 H1975为T790M+L858R双突变株、H3255是仅有L858R的单突变株;各处理组H1975及H3255的存活分数未见明显差异(P=0.952),提示T790M突变对NSCLC细胞株的放射敏感性无影响;2.5 Gy X线辐射组,H1975的IC50为(0.678,2±0.373)μmol/L,较0Gy对照组的(3.520±0.821)μmol/L明显下降,差异有统计学意义(P=0.008),H1975相较于H3255的抗药性也从85.9倍下降为39.2倍。结论电离辐射可降低NSCLC细胞株T790M突变所致的TKI耐药,本实验的研究结果为后续的体内和临床研究提供了研究依据;EGFR-TKI治疗期间联合放射治疗对克服T790M突变介导的耐药性有望成为一种有希望的治疗策略。 |
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| AbstractList | 背景与目的以表皮生长因子受体(epidermal growth factor receptor,EGFR)为靶点的分子靶向治疗在非小细胞肺癌(non-small cell lung cancer,NSCLC)的治疗中发挥重要的作用。EGFR突变的患者对EGFR酪氨酸激酶抑制剂(EGFR-tyrosine kinase inhibitor,EGFR-TKI)治疗敏感、疗效显著,但无论近期疗效如何,患者最终都不可避免地产生耐药。大量研究证实,EGFR基因的二次突变(T790M)是患者耐药的主要原因。本研究旨在探讨电离辐射对NSCLC细胞株T790M突变所致EGFR-TKI耐药的影响。方法选择NSCLC细胞株H1975和H3255为研究对象,实时荧光定量PCR法检测两株细胞的突变状态、克隆形成实验观察两株细胞的放射敏感性,MTT法检测各处理组两株细胞对EGFR-TKI的抗药性。结果 H1975为T790M+L858R双突变株、H3255是仅有L858R的单突变株;各处理组H1975及H3255的存活分数未见明显差异(P=0.952),提示T790M突变对NSCLC细胞株的放射敏感性无影响;2.5 Gy X线辐射组,H1975的IC50为(0.678,2±0.373)μmol/L,较0Gy对照组的(3.520±0.821)μmol/L明显下降,差异有统计学意义(P=0.008),H1975相较于H3255的抗药性也从85.9倍下降为39.2倍。结论电离辐射可降低NSCLC细胞株T790M突变所致的TKI耐药,本实验的研究结果为后续的体内和临床研究提供了研究依据;EGFR-TKI治疗期间联合放射治疗对克服T790M突变介导的耐药性有望成为一种有希望的治疗策略。 背景与目的以表皮生长因子受体（epidermal growth factor receptor, EGFR）为靶点的分子靶向治疗在非小细胞肺癌（non-small cell lung cancer, NSCLC）的治疗中发挥重要的作用。EGFR突变的患者对EGFR酪氨酸激酶抑制剂（EGFR-tyrosine kinase inhibitor, EGFR-TKI）治疗敏感、疗效显著，但无论近期疗效如何，患者最终都不可避免地产生耐药。大量研究证实，EGFR基因的二次突变（T790M）是患者耐药的主要原因。本研究旨在探讨电离辐射对NSCLC细胞株T790M突变所致EGFR-TKI耐药的影响。方法选择NSCLC细胞株H1975和H3255为研究对象，实时荧光定量PCR法检测两株细胞的突变状态、克隆形成实验观察两株细胞的放射敏感性，MTT法检测各处理组两株细胞对EGFR-TKI的抗药性。结果 H1975为T790M+L858R双突变株、H3255是仅有L858R的单突变株；各处理组H1975及H3255的存活分数未见明显差异（P=0.952），提示T790M突变对NSCLC细胞株的放射敏感性无影响；2.5 Gy X线辐射组，H1975的 IC50为（0.678,2±0.373）μmol/L，较0 Gy对照组的（3.520±0.821）μmol/L明显下降，差异有统计学意义（P=0.008），H1975相较于H3255的抗药性也从85.9倍下降为39.2倍。结论电离辐射可降低NSCLC细胞株T790M突变所致的TKI耐药，本实验的研究结果为后续的体内和临床研究提供了研究依据；EGFR-TKI治疗期间联合放射治疗对克服T790M突变介导的耐药性有望成为一种有希望的治疗策略。 |
| Abstract_FL | Background and objectiveEpidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), which targets EGFR, plays an important role in non-small cell lung cancer (NSCLC) treatment. Patients with somatic acti-vating mutations in theEGFR gene exhibit signiifcant initial response but eventually develop resistance to TKI. hTe second mutation (T790M) of theEGFR gene is the possible main cause of drug resistance. hTe aim of this study is to investigate the effect of ionizing radiation on EGFR-TKI resistance caused by T790M mutation in NSCLC cell lines.MethodsWe selected H1975 and H3255 as research subjects and tested the mutation states by real-time PCR analysis. Radiosensitivity was deter-mined by clone-forming test, and drug resistance was detected in different groups by MTT assay.Results H1975 is anEGFR double mutant (L858R plus T790M), whereas H3255 is anEGFR single mutant (L858R). hTe cell survival fractions of H1975 and H3255 did not vary in different treatment groups (P=0.952). hTus, T790M mutation did not affect the radiosensitivity of NSCLC cell lines. hTe IC50 of H1975 in the 2.5 Gy group [(0.678; 2±0.373) μmol/L] was statistically signiifcant compared with that in the 0 Gy normal control group [(3.520±0.821) μmol/L] (P=0.008). hTe drug tolerance of the H1975 cell line by 89.5 dropped to 39.2 times.ConclusionIonizing radiation can reduce TKI resistance caused by T790M mutation in NSCLC cell lines. Our results provide a research basis for futurein vivo and clinical studies. Radiotherapy combined with EGFR-TKI treatment can be a promising strategy to overcome T790M-mediated drug resistance. |
| Author | 李静 武新虎 王振 沈泽天 孙妮 朱锡旭 |
| AuthorAffiliation | 南京大学医学临床学院;南京军区南京总医院 |
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| Author_FL | Zetian SHEN Jing LI Zhen WANG Ni SUN Xinhu WU Xixu ZHU |
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| DocumentTitle_FL | Ionizing Radiation Reduces TKI Resistance Caused by T790M Mutation in NSCLC Cell Lines |
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| Keywords | Radiosensitivity 表皮生长因子受体酪氨酸激酶抑制剂 T790M突变 Drug tolerance 药物耐受性 L858R突变 放射敏感性 L858R mutation EGFR-TKI 肺肿瘤 Lung neoplasms T790M mutation |
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| Notes | Jing LI;Xinhu WU;Zhen WANG;Zetian SHEN;Ni SUN;Xixu ZHU;Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University 12-1395/R |
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| Publisher | 南京大学医学临床学院南京军区南京总医院, 南京,210002 |
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| Snippet | 背景与目的以表皮生长因子受体(epidermal growth factor receptor,EGFR)为靶点的分子靶向治疗在非小细胞肺癌(non-small cell lung cancer,NSCLC)的治疗中发挥重要的作... 背景与目的以表皮生长因子受体（epidermal growth factor receptor, EGFR）为靶点的分子靶向治疗在非小细胞肺癌（non-small cell lung cancer, NSCLC）的治疗中发挥重要的... |
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| SubjectTerms | 肺肿瘤;放射敏感性;表皮生长因子受体酪氨酸激酶抑制剂;药物耐受性;T790M突变;L858R突变 |
| Title | 电离辐射降低NSCLC细胞株T790M突变所致TKI耐药 |
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