Dual Characteristics of Novel HER2 Kinase Domain Mutations in Response to HER2-Targeted Therapies in Human Breast Cancer

• Published in: Clinical cancer research 2016-10, Vol.22 (19), p.4859-4869
• Main Authors: Zuo, Wen-Jia, Jiang, Yi-Zhou, Wang, Yu-Jie, Xu, Xiao-En, Hu, Xin, Liu, Guang-Yu, Wu, Jiong, Di, Gen-Hong, Yu, Ke-Da, Shao, Zhi-Ming
• Format: Article
• Language: English
• Subjects: Animals; Asian Continental Ancestry Group - genetics; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Carcinoma, Ductal, Breast - genetics; Carcinoma, Ductal, Breast - mortality; DNA Mutational Analysis; Drug Resistance, Neoplasm - genetics; Female; Genes, erbB-2 - genetics; Heterografts; Humans; Kaplan-Meier Estimate; Mice; Receptor, ErbB-2 - genetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-15-3036

Somatic mutations in the tyrosine kinase domain of human epidermal growth factor receptor 2 (HER2) may be an alternative mechanism to HER2 activation and can affect the sensitivity toward HER2-targeted therapies. We aimed to investigate the prevalence, clinicopathologic characteristics, and functional relevance of novel HER2 mutations in breast cancer. We performed Sanger sequencing of all exons of the HER2 gene in 1,248 primary tumors and 18 paired metastatic samples. Novel HER2 mutations were functionally characterized. The total HER2 somatic mutation rate was 2.24% (28/1,248). Of the seven novel HER2 mutations, L768S and V773L were only detected in HER2-negative tumors, whereas K753E was found in HER2-positive disease. L768S and V773L mutations exhibited a significant increase in tyrosine kinase-specific activity and strongly increased the phosphorylation of signaling proteins in various cell lines. Xenograft experiments showed that NIH3T3 cells bearing the L768S and V773L mutations displayed more rapid growth. MCF10A, BT474, and MDA-MB-231 cells bearing the K753E mutation were resistant to lapatinib, but could be inhibited by neratinib. Finally, comparison of HER2 mutations in 18 pairs of primary and metastatic lesions revealed that the drug-resistant HER2 mutations (K753E and L755S) were enriched in metastatic lesions. HER2-negative breast cancer with activating mutations can benefit from HER2-targeted therapies. Meanwhile, mutations in the HER2 kinase domain might be a key mechanism of resistance to HER2-targeted therapy, and irreversible tyrosine kinase inhibitors such as neratinib may offer alternative treatment options. Clin Cancer Res; 22(19); 4859-69. ©2016 AACR.