Integrated Transcriptome Analysis Reveals KLK5 and L1CAM Predict Response to Anlotinib in NSCLC at 3rd Line

Area of Science:

• Oncology
• Molecular Biology
• Biomarker Discovery

Background:

• Anlotinib, an oral multi-targeted tyrosine kinase inhibitor (TKI), shows efficacy in third-line treatment for non-small cell lung cancer (NSCLC).
• A subset of NSCLC patients exhibits non-responsiveness to anlotinib, necessitating methods for identifying responsive individuals.
• Identifying predictive biomarkers is crucial for optimizing anlotinib therapy in NSCLC.

Purpose of the Study:

• To screen for potential biomarkers to stratify anlotinib-responsive NSCLC patients using integrated transcriptome analysis.
• To investigate the role of KLK5 and L1CAM as predictive biomarkers for anlotinib response in NSCLC.

Main Methods:

• Differential gene expression analysis between anlotinib-sensitive and resistant NSCLC cell lines (NCI-H1975).
• Kaplan-Meier survival analysis in a TCGA cohort to assess the association of KLK5 and L1CAM expression with clinical outcomes.
• Independent validation of serum KLK5 and L1CAM levels in the ALTER0303 clinical trial cohort (NCT02388919).
• Functional study involving knockdown of KLK5 and L1CAM to evaluate their impact on anlotinib-induced cytotoxicity.

Main Results:

• 1,315 differentially expressed genes were identified between anlotinib-resistant and sensitive NSCLC cells.
• High expression of angiogenesis-related genes KLK5 and L1CAM correlated with poor clinical outcomes in NSCLC patients.
• Elevated serum KLK5 and L1CAM levels were associated with poor anlotinib response in third-line NSCLC patients.
• Knockdown of KLK5 and L1CAM enhanced anlotinib-induced cytotoxicity in resistant cells.

Conclusions:

• Serum levels of KLK5 and L1CAM show potential as predictive biomarkers for stratifying anlotinib response in third-line NSCLC patients.
• Targeting KLK5 and L1CAM may represent a therapeutic strategy to overcome anlotinib resistance in NSCLC.