Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer.
Decreased glutathione biosynthesis contributes to EGFR T790M-driven erlotinib resistance in non-small cell lung cancer.
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谷胱甘肽生物合成减少导致非小细胞肺癌中 EGFR T790M 驱动的厄洛替尼耐药
DOI：
10.1038/celldisc.2016.31
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发表时间：
2016
期刊：
影响因子：
33.5
通讯作者：
Pardo, Olivier E.
中科院分区：
文献类型：
--
作者：
Li, Hongde;Stokes, William;Chater, Emily;Roy, Rajat;de Bruin, Elza;Hu, Yili;Liu, Zhigang;Smit, Egbert F.;Heynen, Guus J. J. E.;Downward, Julian;Seckl, Michael J.;Wang, Yulan;Tang, Huiru;Pardo, Olivier E.
表皮生长因子受体（EGFR）抑制剂如厄洛替尼是治疗EGFR驱动型肺癌的新型有效药物，但其临床效果往往因继发性T790M EGFR突变而获得性耐药而受损。为了克服这一问题，我们分析了两对独立的厄洛替尼敏感/耐药细胞之间的代谢组学差异，发现T790M EGFR细胞中的谷胱甘肽（GSH）水平显著降低。我们还发现，厄洛替尼耐药细胞中GSH水平的增加使它们重新敏感，而厄洛替尼敏感细胞中GSH水平的降低使它们产生耐药性。由于NRF2的抑制，GSH合成酶（GCLC和GSS）的转录减少，导致抗性细胞中GSH水平降低，这与T790M突变直接相关。T790M EGFR临床样品也显示这些关键酶的表达降低；用小分子GST抑制剂增加肿瘤内GSH水平，使小鼠耐药肿瘤对厄洛替尼重新敏感。因此，我们确定了一种由EGFR T790M控制的新的耐药途径，并在临床中找到了解决这一问题的治疗策略。
Epidermal growth factor receptor (EGFR) inhibitors such as erlotinib are novel effective agents in the treatment of EGFR-driven lung cancer, but their clinical impact is often impaired by acquired drug resistance through the secondary T790M EGFR mutation. To overcome this problem, we analysed the metabonomic differences between two independent pairs of erlotinib-sensitive/resistant cells and discovered that glutathione (GSH) levels were significantly reduced in T790M EGFR cells. We also found that increasing GSH levels in erlotinib-resistant cells re-sensitised them, whereas reducing GSH levels in erlotinib-sensitive cells made them resistant. Decreased transcription of the GSH-synthesising enzymes (GCLC and GSS) due to the inhibition of NRF2 was responsible for low GSH levels in resistant cells that was directly linked to the T790M mutation. T790M EGFR clinical samples also showed decreased expression of these key enzymes; increasing intra-tumoural GSH levels with a small-molecule GST inhibitor re-sensitised resistant tumours to erlotinib in mice. Thus, we identified a new resistance pathway controlled by EGFR T790M and a therapeutic strategy to tackle this problem in the clinic.
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影响因子：
4.3
作者：
Cavill R;Kamburov A;Ellis JK;Athersuch TJ;Blagrove MS;Herwig R;Ebbels TM;Keun HC
通讯作者：
Keun HC
DOI：
10.1074/jbc.m115.660498
发表时间：
2015-07-10
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Makinoshima H;Takita M;Saruwatari K;Umemura S;Obata Y;Ishii G;Matsumoto S;Sugiyama E;Ochiai A;Abe R;Goto K;Esumi H;Tsuchihara K
通讯作者：
Tsuchihara K
影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
DOI：
10.1016/j.bbrc.2012.12.070
发表时间：
2013-02-15
影响因子：
3.1
作者：
Chen, Gang;Kronenberger, Peter;De Greve, Jacques
通讯作者：
De Greve, Jacques
影响因子：
51.1
作者：
Miller, Vincent A.;Hirsh, Vera;Yang, James Chih-Hsin
通讯作者：
Yang, James Chih-Hsin