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首页> 外文期刊>Journal of cellular biochemistry. >gamma Secretase Inhibitor BMS-708163 Reverses Resistance to EGFR Inhibitor via the PI3K/Akt Pathway in Lung Cancer
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gamma Secretase Inhibitor BMS-708163 Reverses Resistance to EGFR Inhibitor via the PI3K/Akt Pathway in Lung Cancer

机译：γ分泌酶抑制剂BMS-708163通过PI3K / Akt通路逆转肺癌对EGFR抑制剂的耐药性

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摘要

Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitor (TKI). Acquired resistance to EGFR TKI develops after prolonged treatment. The aim of this study was to investigate the effect of the novel gamma secretase inhibitor BMS-708163 on acquired resistance to the EGFR TKI gefitinib. We did not observe known mechanisms of acquired resistance to EGFR TKI, including the EGFR T790M mutation and MET gene amplification in the gefitinib-resistant PC9/AB2 cells. BMS-708163 inhibited PI3K/Akt expression and sensitized PC9/AB2 cells to gefitinib-induced cytotoxicity. In contrast, BMS-708163 had no significant effect on gefitinib sensitivity in PC9 parental cells. Combined treatment with BMS-708163 and gefitinib induced high levels of apoptosis. Our in vivo studies showed that combined treatment of gefitinib and BMS-708163 inhibited the growth of PC9/AB2 xenografts. In conclusion, our data show that combined treatment of gefitinib and gamma secretase inhibitors may be useful for treating lung adenocarcinomas harboring EGFR mutations with acquired gefitinib resistance. (C) 2015 Wiley Periodicals, Inc.
机译：带有表皮生长因子受体（EGFR）突变的肺腺癌细胞对EGFR酪氨酸激酶抑制剂（TKI）敏感。长时间治疗后会产生对EGFR TKI的耐药性。这项研究的目的是研究新型γ分泌酶抑制剂BMS-708163对获得性对EGFR TKI吉非替尼耐药的作用。我们没有观察到已知的获得性抗EGFR TKI的机制，包括在耐吉非替尼的PC9 / AB2细胞中的EGFR T790M突变和MET基因扩增。 BMS-708163抑制PI3K / Akt表达并使PC9 / AB2细胞对吉非替尼诱导的细胞毒性敏感。相反，BMS-708163对PC9亲本细胞中的吉非替尼敏感性没有明显影响。 BMS-708163和吉非替尼联合治疗可诱导高水平的细胞凋亡。我们的体内研究表明，吉非替尼和BMS-708163的联合治疗可抑制PC9 / AB2异种移植物的生长。总之，我们的数据表明，吉非替尼和伽马分泌酶抑制剂的联合治疗可能可用于治疗具有EGFR突变的吉非替尼耐药的肺腺癌。 （C）2015威利期刊公司

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