WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors
WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors
复制标题
DOI：
10.1038/labinvest.2011.187
复制
发表时间：
2012-03-01
影响因子：
5
通讯作者：
Miyagi, Yohei
中科院分区：
文献类型：
--
作者：
Sakuma, Yuji;Yamazaki, Yukiko;Miyagi, Yohei
SRC在肺腺癌的失巢细胞抵抗中起一定作用。我们以两种表皮生长因子受体(EGFR)突变的肺腺癌细胞系HCC827(E746-A750缺失)和H1975(L858R+T790M)悬液中的细胞为研究对象，以阐明长期使用Src酪氨酸激酶抑制剂(TKIs)能否根除悬浮的肺腺癌细胞。我们还检测了16例EGFR突变的肺腺癌患者转移阳性淋巴结中突变特异性EGFR的免疫组织化学表达。AZD0530、曲古抑菌素A(TSA)和ABT-263联合作用144h后，几乎所有悬浮的HCC827细胞都发生了凋亡，但许多悬浮的H1975细胞存活下来。AZD0530是一种Src TKI，TSA是一种组蛋白去乙酰化酶抑制剂，ABT-263是一种Bcl-2抑制剂。在治疗过程中，HCC827细胞中EGFR的磷酸化水平降低，而在H1975细胞中保持稳定。第三代EGFR TKI WZ4002完全抑制了抗Src TKI的H1975细胞和HCC827细胞的磷酸化EGFR。因此，在WZ4002、ABT-263和TSA的联合作用下，这两种悬浮细胞株在144h内几乎完全被消灭。有趣的是，处理过的悬浮细胞比贴壁细胞经历了更大程度的凋亡。淋巴结内漂浮肺腺癌细胞表达突变型EGFR。这些发现表明，悬浮的EGFR突变的肺腺癌细胞比附着的细胞更依赖于EGFR的激活来生存。表达突变特异性EGFR的血管内循环的肿瘤细胞对WZ4002、ABT-263和TSA的联合治疗高度敏感。实验室调查(2012年)92,371-383；doi：10.1038/Labinvest.2011.187；2011年12月12日在线发布
Src has a role in the anoikis resistance in lung adenocarcinomas. We focused on two epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cell lines, HCC827 (E746-A750 deletion) and H1975 (L858R+T790M), in suspension to elucidate whether suspended lung adenocarcinoma cells are eradicated by long-term treatment with Src tyrosine kinase inhibitors (TKIs). We also examined metastasis-positive lymph nodes from 16 EGFR-mutant lung adenocarcinoma patients for immunohistochemical expression of mutant-specific EGFR. Almost all suspended HCC827 cells underwent apoptosis after 144 h of combination treatment with AZD0530, trichostatin A (TSA), and ABT-263, whereas many suspended H1975 cells survived the treatment. AZD0530 is a Src TKI, TSA is a histone deacetylase inhibitor, and ABT-263 is a Bcl-2 inhibitor. During the therapy, the phosphorylation of EGFR decreased in HCC827 cells and remained stable in H1975 cells. The phosphorylated EGFR of Src TKI-resistant H1975 cells, as well as HCC827 cells, was completely suppressed by the third generation EGFR TKI, WZ4002. Consequently, both the suspended cell lines were almost completely eradicated within 144 h, with the combined therapy of WZ4002, ABT-263, and TSA. Interestingly, treated suspended cells underwent apoptosis to a greater extent than did adherent cells. Intrasinus floating lung adenocarcinoma cells in the lymph nodes expressed a mutant-specific EGFR. These findings suggest that suspended EGFR-mutant lung adenocarcinoma cells depend significantly more on EGFR activation for survival than attached cells do. The tumor cells circulating in vessels, which express mutant-specific EGFR, would be highly susceptible to the combination therapy of WZ4002, ABT-263, and TSA. Laboratory Investigation (2012) 92, 371-383; doi:10.1038/labinvest.2011.187; published online 12 December 2011