HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation.
HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation.
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DOI：
10.1158/2159-8290.cd-12-0108
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发表时间：
2012-10
期刊：
影响因子：
28.2
通讯作者：
Pao W
中科院分区：
文献类型：
--
作者：
Takezawa K;Pirazzoli V;Arcila ME;Nebhan CA;Song X;de Stanchina E;Ohashi K;Janjigian YY;Spitzler PJ;Melnick MA;Riely GJ;Kris MG;Miller VA;Ladanyi M;Politi K;Pao W
EGFR突变肺癌最终对EGFR酪氨酸激酶抑制剂（TKIs）治疗产生耐药性。EGFR-TKI阿法替尼联合抗egfr抗体西妥昔单抗可克服小鼠模型和人患者的获得性耐药。由于阿法替尼也是一种有效的HER2抑制剂，我们研究了HER2在egfr突变肿瘤细胞中的作用。我们在体外和体内表明，阿法替尼加西妥昔单抗显著抑制HER2磷酸化。在所有研究的细胞系模型中，HER2过表达或敲低分别赋予抗性或敏感性。荧光原位杂交分析显示，HER2在12%的获得性耐药肿瘤中扩增，而在未经治疗的肺腺癌中仅扩增1%。值得注意的是，HER2扩增和EGFR T790M是相互排斥的。总的来说，这些结果揭示了一种以前未被认识到的EGFR TKIs耐药机制，并为评估EGFR突变肿瘤中获得性EGFR TKIs耐药的状态和可能的靶向HER2提供了依据。
EGFR-mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKIs). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models and human patients. Since afatinib is also a potent HER2 inhibitor, we investigated the role of HER2 in EGFR-mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. Fluorescent in situ hybridization analysis revealed that HER2 was amplified in 12% of tumors with acquired resistance versus only 1% of untreated lung adenocarcinomas. Notably, HER2 amplification and EGFR T790M were mutually exclusive. Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR mutant tumors with acquired resistance to EGFR TKIs.