Department of Medicine, Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 37232, USA.
Cancer Discov. 2012 Oct;2(10):922-33. doi: 10.1158/2159-8290.CD-12-0108. Epub 2012 Sep 5.
EGF receptor (EGFR)-mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKI). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models and human patients. Because 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. FISH 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.
表皮生长因子受体（EGFR）-突变型肺癌最终会对 EGFR 酪氨酸激酶抑制剂（TKI）产生耐药性。EGFR-TKI 阿法替尼与抗 EGFR 抗体西妥昔单抗的联合使用可以克服小鼠模型和人类患者中获得性耐药。因为阿法替尼也是一种有效的 HER2 抑制剂，所以我们研究了 HER2 在 EGFR 突变型肿瘤细胞中的作用。我们在体外和体内都证明了阿法替尼联合西妥昔单抗可以显著抑制 HER2 的磷酸化。在所有研究的细胞系模型中，HER2 的过表达或敲低分别赋予了耐药性或敏感性。FISH 分析显示，获得性耐药的肿瘤中有 12%存在 HER2 扩增，而未经治疗的肺腺癌中只有 1%存在 HER2 扩增。值得注意的是，HER2 扩增和 EGFR(T790M)是相互排斥的。综上所述，这些结果揭示了一种以前未知的 EGFR-TKI 耐药机制，并为评估 EGFR-TKI 获得性耐药的 EGFR 突变型肿瘤中 HER2 的状态和可能的靶向治疗提供了依据。
