c-Src Increases the Sensitivity to TKIs in the EGFR-Mutant Lung Adenocarcinoma.
c-Src Increases the Sensitivity to TKIs in the EGFR-Mutant Lung Adenocarcinoma.
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c-Src 增加 EGFR 突变肺腺癌对 TKI 的敏感性
DOI：
10.3389/fonc.2021.602900
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发表时间：
2021
影响因子：
4.7
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Min W;He C;Zhang S;Zhao Y
c-Src和表皮生长因子受体（EGFR）是控制细胞对微环境线索的反应的关键顶端激酶。c-Src如何影响EGFR相关信号传导和靶向治疗仍然难以捉摸。最初，caspase-8在酪氨酸380磷酸化的c-Src主要增强c-Src激活，以促进肺腺癌通过获得上皮间质转化（EMT）表型转移。从机制上讲，与其他c-Src伴侣蛋白相比，c-Src SH 2结构域与caspase-8的磷酸酪氨酸380以及SH 3结构域与caspase-8的“PDEP”基序的连接过度激活了c-Src。c-Src不能触发EGFR相关信号。磷酸酪氨酸1068、1086和1145的水平反映了这一点，这些水平对c-Src活化没有影响。酪氨酸激酶抑制剂（TKI）抑制EGFR相关信号传导，通过坏死性凋亡和内源性凋亡导致肺腺癌细胞死亡。鉴于c-Src活化在肺腺癌中很常见，通过达沙替尼阻断c-Src活化可以通过EGFR的SH 2结构域封闭EGFR的生存信号相关磷酸酪氨酸，从而增加TKI在EGFR突变型肺腺癌中的抗肿瘤活性。总之，达沙替尼给药导致c-Src失活可使EGFR突变型肺腺癌对TKI敏感。
c-Src and the epidermal growth factor receptor (EGFR) are key apical kinases that govern cell responses to microenvironmental cues. How c-Src affects EGFR-related signaling and targeted therapy remains elusive. Initially, caspase-8 phosphorylated at tyrosine 380 by c-Src predominantly enhancing c-Src activation to facilitate metastasis through attaining epithelial-mesenchymal transition (EMT) phenotype in lung adenocarcinoma. Mechanistically, the linkage of c-Src SH2 domain with phosphotyrosine 380 of caspase-8 and SH3 domain with “PDEP” motif of caspase-8 overactivates c-Src as compared with other c-Src-partner proteins. c-Src is incapable of triggering EGFR-related signaling. This is reflected by the levels of phosphotyrosine 1068, 1086, and 1145, which have no impact on c-Src activation. Tyrosine kinase inhibitors (TKIs) suppress EGFR-related signaling to yield cell deaths of lung adenocarcinoma by both necroptosis and intrinsic apoptosis. Given that c-Src activation is frequent in lung adenocarcinoma, blocking c-Src activation through dasatinib can seal the survival-signaling-related phosphotyrosines of EGFR by its SH2 domain, which in turn increases the antitumor activity of TKIs in EGFR-mutant lung adenocarcinoma. Collectively, c-Src inactivation by dasatinib administration sensitizes EGFR-mutant lung adenocarcinoma to TKIs.
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