Resistance Mechanism against Trastuzumab in HER2-Positive Cancer Cells and Its Negation by Src Inhibition
Resistance Mechanism against Trastuzumab in HER2-Positive Cancer Cells and Its Negation by Src Inhibition
复制标题
DOI：
10.1158/1535-7163.mct-16-0669
复制
发表时间：
2017-06-01
影响因子：
5.7
通讯作者：
Oh, Do-Youn
中科院分区：
文献类型：
--
作者：
Jin, Mei Hua;Nam, Ah-Rong;Oh, Do-Youn
曲妥珠单抗联合化疗是人类表皮生长因子受体2(HER2)阳性乳腺癌和胃癌患者的标准护理。对抗HER2治疗的几种耐药机制已经提出。SRC的激活被认为与HER2阳性乳腺癌的耐药性有关。在我们的研究中，我们从HER2扩增的胃和胆道癌细胞株(SNU-216、NCI-N87、SNU-2670和SNU-2773)中获得了四个曲妥珠单抗耐药(HR)癌细胞株。SNU2670HR和NCI-N87HR细胞中的Src磷酸化水平升高，而SNU216HR和SNU2773HR细胞中未见此现象。在SNU216HR和SNU2773HR细胞系中，粘着斑激酶磷酸化水平升高。博苏替尼作为一种Src抑制剂，抑制了亲代和HR细胞系的生长、细胞周期进展和迁移。具体地说，Src与FAK相互作用，影响AKT、ERK和STAT3等下游分子。在Src激活的HR细胞系中，博苏替尼显示出比亲代细胞系更强的抗肿瘤作用。综上所述，这项研究提示，抑制Src可能是克服HER2阳性癌症患者曲妥珠单抗耐药性的有效措施。(C)2017年AACR。
Trastuzumab in combination with chemotherapy is the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancers. Several resistance mechanisms against anti-HER2 therapy have been proposed. Src activation has been suggested to be responsible for the resistance of HER2-positive breast cancer. In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from HER2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773). Elevated Src phosphorylation was detected in SNU2670HR and NCI-N87HR cell lines, but not in SNU216HR or SNU2773HR cell lines. In SNU216HR and SNU2773HR cell lines, phospho-FAK (focal adhesion kinase) was elevated. Bosutinib as a Src inhibitor suppressed growth, cell-cycle progression, and migration in both parental and HR cell lines. Specifically, Src interacted with FAK to affect downstream molecules such as AKT, ERK, and STAT3. Bosutinib showed more potent antitumor effects in Src-activated HR cell lines than parental cell lines. Taken together, this study suggests that Src inhibition may be an effective measure to overcome trastuzumab resistance in HER2-positive cancer. (C) 2017 AACR.