EGFR, HER2 and HER3 dimerization patterns guide targeted inhibition in two histotypes of esophageal cancer
EGFR, HER2 and HER3 dimerization patterns guide targeted inhibition in two histotypes of esophageal cancer
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DOI：
10.1002/ijc.28771
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发表时间：
2014-10-01
影响因子：
6.4
通讯作者：
Lassmann, Silke
中科院分区：
文献类型：
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作者：
Fichter, Christiane Daniela;Timme, Sylvia;Lassmann, Silke
受体酪氨酸激酶（RTKs）是上皮性肿瘤靶向治疗的重点。我们的研究探讨了在治疗性EGFR和HER2抑制剂的背景下，EGFR、HER2和HER3在食管癌原位和体外表达和二聚化的作用。在食管癌（n=110）的档案预处理活检中，EGFR在食管鳞状细胞癌（escc）中优先表达（22.4%,p=0.088），在食管（Barrett）腺癌（EACs）中优先表达HER2 （34.4%, p < 0.001）和HER3 （91.5%, p < 0.001）。原位接近结扎实验显示，ESCC和EAC分别以EGFR和HER2同型二聚体为主。然而，EAC病例也表现出HER2/HER3异源二聚体。体外ESCC （OE21）细胞对厄洛替尼、吉非替尼和拉帕替尼表现出显著的应答，AKT磷酸化缺失，G0/G1细胞周期阻滞，诱导凋亡。在EAC细胞（OE19、OE33和SK-GT-4）中，拉帕替尼对强HER2阳性（主要是HER2同型二聚体和一些HER2/EGFR异源二聚体）OE19和OE33细胞同样有效。单独给予her2靶向抗体（曲妥珠单抗和帕妥珠单抗）在ESCC和EAC细胞中基本无效。然而，这两种抗体在EAC （OE19和OE33）细胞与外周血单核细胞共培养时均显著诱导抗体依赖性细胞毒性。该研究表明，EGFR和HER2的过表达主要导致escc和EACs中的同型二聚体分别出现。然而，一些EACs也表现出HER2的二聚化可塑性，例如与HER3的二聚化。这种RTK二聚化模式影响体外ESCC和EAC细胞对EGFR和HER2靶向抑制剂的反应，因此可能影响未来对EACs中特别是HER2靶向抑制剂的预测。
Receptor tyrosine kinases (RTKs) are in the focus of targeted therapy for epithelial tumors. Our study addressed the role of EGFR, HER2 and HER3 expression and dimerization in esophageal cancers in situ and in vitro in the context of therapeutic EGFR and HER2 inhibitors. In archival pretreatment biopsies of esophageal carcinomas (n=110), EGFR was preferentially expressed in esophageal squamous cell carcinomas (ESCCs) (22.4%; p=0.088) and HER2 (34.4%; p < 0.001) with HER3 (91.5%; p < 0.001) in esophageal (Barrett's) adenocarcinomas (EACs). In situ proximity ligation assays revealed mainly EGFR and HER2 homodimers in ESCC and EAC cases, respectively. However, EAC cases also exhibited HER2/HER3 heterodimers. In vitro ESCC (OE21) cells displayed a significant response to erlotinib, gefitinib and lapatinib, with loss of AKT phosphorylation, G0/G1 cell cycle arrest and induction of apoptosis. In EAC cells (OE19, OE33 and SK-GT-4), lapatinib was similarly effective in strongly HER2-positive (mainly HER2 homodimers and some HER2/EGFR heterodimers) OE19 and OE33 cells. The HER2-targeting antibodies (trastuzumab and pertuzumab) given alone were largely ineffective in ESCC and EAC cells. However, both antibodies significantly induced antibody-dependent cellular cytotoxicity in EAC (OE19 and OE33) cells upon co-culture with peripheral blood mononuclear cells. The study reveals that overexpression of EGFR and HER2 predominantly results in homodimers in ESCCs and EACs, respectively. Still, some EACs also show HER2 dimerization plasticity, e. g., with HER3. Such RTK dimerization patterns affect responses to EGFR and HER2 targeting inhibitors in ESCC and EAC cells in vitro and hence may influence future prediction for particularly HER2-targeting inhibitors in EACs.