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Increased expression of SSEA-4 on TKI-resistant non-small cell lung cancer with EGFR-T790M mutation
Nai-Yu Chen1,2, Chih-Wei Lin3,4, Ting-Yen Lai1
1Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
Abstract:
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 β3GalT5 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.
Insights
Targeting SSEA-4, a biomarker in drug-resistant non-small cell lung cancer (NSCLC) with EGFR mutations, offers a new treatment strategy. A SSEA-4 targeted antibody shows promise in preclinical studies for overcoming TKI resistance.
Area of Science:
- Oncology
- Glycobiology
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer death, with tyrosine kinase inhibitors (TKIs) being a common treatment.
- Acquired resistance to TKIs, often due to the EGFR-T790M mutation, presents a significant clinical challenge, affecting approximately 60% of resistant cases.
- Identifying novel therapeutic targets is crucial for improving outcomes in TKI-resistant NSCLC.
Purpose of the Study:
- To investigate alternative therapeutic targets for NSCLC resistant to TKIs, specifically in cases with the EGFR-T790M mutation.
- To evaluate the role of globo-series glycosphingolipids, particularly stage-specific embryonic antigen-4 (SSEA-4), as potential biomarkers and therapeutic targets.
- To assess the efficacy of a SSEA-4 targeted monoclonal antibody in preclinical models of TKI-resistant NSCLC.
Main Methods:
- Comparative analysis of globo-series glycosphingolipid expression in TKI-sensitive versus TKI-resistant NSCLC cell lines with EGFR-T790M mutation.
- Quantification of SSEA-4 and β3GalT5 expression in NSCLC cell lines and correlation with patient survival data.
- In vitro and in vivo efficacy studies of a SSEA-4 targeted monoclonal antibody, including a homogeneous glycoform with optimized Fc glycan.
Main Results:
- Increased expression of globo-series glycosphingolipids, most significantly SSEA-4, was observed in TKI-resistant NSCLC cell lines with EGFR-T790M mutation.
- Higher expression of SSEA-4 and the synthesizing enzyme β3GalT5 was found in resistant cell lines and correlated with poor patient survival.
- A SSEA-4 targeted monoclonal antibody demonstrated high efficacy against TKI-resistant NSCLC in cell-based and animal models.
Conclusions:
- SSEA-4 is a promising biomarker for predicting tumor recurrence and identifying patients with TKI-resistant NSCLC harboring the EGFR-T790M mutation.
- Targeting SSEA-4 with a specifically designed monoclonal antibody represents a potential therapeutic strategy to overcome TKI resistance in NSCLC.
- These findings pave the way for novel treatment approaches and improved patient outcomes in a challenging subset of lung cancer.
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