journal contribution
posted on 2023-03-31, 20:22 authored by Wen-Jia Zuo, Yi-Zhou Jiang, Yu-Jie Wang, Xiao-En Xu, Xin Hu, Guang-Yu Liu, Jiong Wu, Gen-Hong Di, Ke-Da Yu, Zhi-Ming Shao Supplementary Table S1. Sanger sequencing primers for all 27 exons of HER2 gene. Supplementary Table S2. Clinicopathologic characteristics of breast cancer patients enrolled in our study. Supplementary Table S3. Clinicopathologic characteristics of HER2-mutated breast cancer. Supplementary Table S4. Clinical information of patients with HER2-mutated breast cancer
Funding
Fudan University
National Natural Science Foundation of China
Municipal Project for Developing Emerging and Frontier Technology
Project of Conquering Major Diseases in Shanghai Municipality Health
Innovation Team of Ministry of Education
Shanghai Key Laboratory of Breast Cancer
History
ARTICLE ABSTRACT
Purpose: 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.Experimental Design: 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.Results: 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.Conclusions: 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.
