HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer.
HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer.
复制标题
DOI：
10.1016/j.molonc.2014.10.011
复制
发表时间：
2015-03
影响因子：
6.6
通讯作者：
Esteva FJ
中科院分区：
文献类型：
--
作者：
Boulbes DR;Arold ST;Chauhan GB;Blachno KV;Deng N;Chang WC;Jin Q;Huang TH;Hsu JM;Brady SW;Bartholomeusz C;Ladbury JE;Stone S;Yu D;Hung MC;Esteva FJ
对HER 2靶向治疗的耐药性仍然是治疗HER 2过表达乳腺癌的主要障碍。了解有助于耐药性发展的分子途径是必要的，以提高新药物的临床效用，并预测基于肿瘤特异性突变的靶向个性化治疗的成功。关于HER家族突变在乳腺癌中的临床意义知之甚少。由于HER 1/EGFR内的突变可预测肺癌对酪氨酸激酶抑制剂（TKI）的反应，我们研究了HER家族激酶结构域的突变是否可预测HER 2过表达乳腺癌对靶向治疗的反应。我们对76例HER 2过表达的浸润性癌的HER家族激酶结构域进行了测序，并鉴定了12种错义变体。肿瘤携带任何这些突变的患者在转移性背景下对HER 2导向治疗无应答。我们开发了突变细胞系，并使用结构分析来确定蛋白质构象的变化是否可以解释对治疗缺乏反应。我们还对所有HER 2突变体进行了功能研究，结果表明它们具有侵袭性表型，并改变了TKI拉帕替尼的作用。我们的数据表明，在微调HER激酶结构域的突变在乳腺癌进展中发挥关键作用，并可能作为预后和预测标志物。
Resistance to HER2-targeted therapies remains a major obstacle in the treatment of HER2-overexpressing breast cancer. Understanding the molecular pathways that contribute to the development of drug resistance is needed to improve the clinical utility of novel agents, and to predict the success of targeted personalized therapy based on tumor-specific mutations. Little is known about the clinical significance of HER family mutations in breast cancer. Because mutations within HER1/EGFR are predictive of response to tyrosine kinase inhibitors (TKI) in lung cancer, we investigated whether mutations in HER family kinase domains are predictive of response to targeted therapy in HER2-overexpressing breast cancer. We sequenced the HER family kinase domains from 76 HER2-overexpressing invasive carcinomas and identified 12 missense variants. Patients whose tumors carried any of these mutations did not respond to HER2 directed therapy in the metastatic setting. We developed mutant cell lines and used structural analyses to determine whether changes in protein conformation could explain the lack of response to therapy. We also functionally studied all HER2 mutants and showed that they conferred an aggressive phenotype and altered effects of the TKI lapatinib. Our data demonstrate that mutations in the finely tuned HER kinase domains play a critical function in breast cancer progression and may serve as prognostic and predictive markers.