EGFR-TKI-induced HSP70 degradation and BER suppression facilitate the occurrence of the EGFR T790 M resistant mutation in lung cancer cells.
EGFR-TKI-induced HSP70 degradation and BER suppression facilitate the occurrence of the EGFR T790 M resistant mutation in lung cancer cells.
复制标题
EGFR-TKI诱导的HSP70降解和BER抑制促进肺癌细胞中EGFR T790 M耐药突变的发生
DOI：
10.1016/j.canlet.2018.03.004
复制
发表时间：
2018-06-28
期刊：
影响因子：
9.7
通讯作者：
Yin Z
中科院分区：
文献类型：
--
作者：
Cao X;Zhou Y;Sun H;Xu M;Bi X;Zhao Z;Shen B;Wan F;Hong Z;Lan L;Luo L;Guo Z;Yin Z
携带EGFR激活突变的非小细胞肺癌（NSCLC）患者最初对EGFR酪氨酸激酶抑制剂（EGFR-TKI）有反应，并显示出良好的结局。然而，几乎所有患者都出现了对EGFR-TKI的获得性耐药，主要是由于EGFR T790 M突变。在这里，我们发现，低剂量EGFR-TKI治疗导致HCC 827细胞中EGFR T790 M突变的出现和HSP 70蛋白水平的降低。厄洛替尼治疗抑制HSP 70在酪氨酸41处的磷酸化并增加HSP 70泛素化，导致HSP 70降解。我们发现EGFR-TKI治疗导致DNA损伤增加和基因突变率增加，这是继发于EGFR-TKI诱导的HSP 70蛋白减少。重要的是，HSP 70过表达延迟了厄洛替尼诱导的EGFR T790 M突变的发生。我们进一步证明，热休克蛋白70相互作用的多个酶的碱基切除修复（BER）的途径，并促进不仅是效率，但也保真度BER。总的来说，我们的研究结果表明，EGFR-TKI治疗通过诱导HSP 70蛋白降解减弱BER促进基因突变和EGFR T790 M继发突变的出现。
Non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations initially respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and have shown favorable outcomes. However, acquired drug resistance to EGFR-TKIs develops in almost all patients mainly due to the EGFR T790M mutation. Here, we show that treatment with low-dose EGFR-TKI results in the emergence of the EGFR T790M mutation and in the reduction of HSP70 protein levels in HCC827 cells. Erlotinib treatment inhibits HSP70 phosphorylation at tyrosine 41 and increases HSP70 ubiquitination, resulting in HSP70 degradation. We show that EGFR-TKI treatment causes increased DNA damage and enhanced gene mutation rates, which are secondary to the EGFR-TKI-induced reduction of HSP70 protein. Importantly, HSP70 overexpression delays the occurrence of Erlotinib-induced EGFR T790M mutation. We further demonstrate that HSP70 interacts with multiple enzymes in the base excision repair (BER) pathway and promotes not only the efficiency but also the fidelity of BER. Collectively, our findings show that EGFR-TKI treatment facilitates gene mutation and the emergence of EGFR T790M secondary mutation by the attenuation of BER via induction of HSP70 protein degradation.
登录
查看更多内容
影响因子：
11.4
作者：
Kubota, Y;Nash, RA;Lindahl, T
通讯作者：
Lindahl, T
影响因子：
4.8
作者：
Kenny, MK;Mendez, F;Bases, R
通讯作者：
Bases, R
DOI：
10.1158/1078-0432.ccr-10-2277
发表时间：
2011-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Arcila ME;Oxnard GR;Nafa K;Riely GJ;Solomon SB;Zakowski MF;Kris MG;Pao W;Miller VA;Ladanyi M
通讯作者：
Ladanyi M
影响因子：
11.2
作者：
Daugaard, Mads;Kirkegaard-Sorensen, Thomas;Jaattela, Marja
通讯作者：
Jaattela, Marja
影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B