Boulbes Delphine R, Arold Stefan T, Chauhan Gaurav B, Blachno Korina V, Deng Nanfu, Chang Wei-Chao, Jin Quanri, Huang Tzu-Hsuan, Hsu Jung-Mao, Brady Samuel W, Bartholomeusz Chandra, Ladbury John E, Stone Steve, Yu Dihua, Hung Mien-Chie, Esteva Francisco J
Departments of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Departments of Biochemistry & Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Departments of Center for Biomolecular Structure and Function, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Division of Biological and Environmental Sciences and Engineering, Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
Mol Oncol. 2015 Mar;9(3):586-600. doi: 10.1016/j.molonc.2014.10.011. Epub 2014 Nov 11.
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.
对HER2靶向治疗的耐药性仍然是HER2过表达乳腺癌治疗中的主要障碍。为了提高新型药物的临床应用价值，并基于肿瘤特异性突变预测靶向个性化治疗的成功率，需要了解导致耐药性产生的分子途径。目前对乳腺癌中HER家族突变的临床意义知之甚少。由于HER1/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家族激酶结构域中的突变是否可预测HER2过表达乳腺癌对靶向治疗的反应。我们对76例HER2过表达浸润性癌的HER家族激酶结构域进行了测序，鉴定出12个错义变体。肿瘤携带这些突变中的任何一种的患者在转移情况下对HER2导向治疗无反应。我们构建了突变细胞系，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无反应的原因。我们还对所有HER2突变体进行了功能研究，结果表明它们赋予了侵袭性表型，并改变了TKI拉帕替尼的作用效果。我们的数据表明，精细调节的HER激酶结构域中的突变在乳腺癌进展中起关键作用，可能作为预后和预测标志物。
