Increased expression of SSEA-4 on TKI- resistant non-small cell lung cancer with EGFR-T790M mutation
成果类型：
Article
署名作者：
Chen, Nai- Yu; Lin, Chih- Wei; Lai, Ting- Yen; Wu, Chung-Yi; Liao, Pei-Chi; Hsu, Tsui-Ling; Wong, Chi-Huey
署名单位：
Academia Sinica - Taiwan; National Yang Ming Chiao Tung University; China Medical University Taiwan; China Medical University Taiwan; Scripps Research Institute
刊物名称：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN/ISSBN：
0027-15203
DOI：
10.1073/pnas.2313397121
发表日期：
2024-01-30
关键词：
growth-factor receptor
embryonic stem-cell
fc-gamma-riii
breast-cancer
globo-h
antibody
mechanisms
series
glycosylation
binding
摘要：
Non-small cell lung cancer (NSCLC), a major life-threatening disease accounting for 85% of all lung cancer cases, has been treated with tyrosine kinase inhibitors (TKIs), but often resulted in drug resistance, and approximately 60% of TKI-resistant cases are due to acquired secondary (epithelial growth factor receptor) EGFR-T790M mutation. To identify alternative targets for TKI-resistant NSCLC with EGFR-T790M mutation, we found that the three globo - series glycosphingolipids are increasingly expressed on this type of NSCLC cell lines, and among them, the increase of stage-specific embryonic antigen - 4 (SSEA-4) expression is the most significant. Compared to TKI-sensitive cell lines, SSEA-4 and the key enzyme (33GalT5 responsible for the synthesis of SSEA3 are more expressed in TKI-resistant NSCLC cell lines with EGFR-T790M mutation, and the expression levels strongly correlate with poor survival in patients with EGFR mutation. In addition, we demonstrated that a SSEA-4 targeted monoclonal antibody, especially the homogeneous glycoform with well-defined Fc glycan designed to improve effective functions, is highly effective against this subpopulation of NSCLC in cell-based and animal studies. These findings provide a direction for the prediction of tumor recurrence and treatment of TKI-resistant NSCLC with EGFR-T790M mutation.