FGA isoform as an indicator of targeted therapy for EGFR mutated lung adenocarcinoma
Zhi Shang1, Xiaomin Niu2, Kewei Zhang3
1State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
Abstract:
Epidermal growth factor receptor (EGFR) gene is frequently mutated in non-small cell lung cancer (NSCLC), which can be targeted by EGFR tyrosine kinase inhibitors (TKIs). It is hard, however, to monitor the performance of EGFR-TKI therapy dynamically. Therefore, therapeutic indicators are urgently needed. Novel antibody microarray, containing 41,472 antibodies, was used for comprehensive analyzing of serum samples from 9 normal subjects and 9 EGFR mutated lung adenocarcinoma patients at three EGFR-TKI treatment time points, including before treatment (Baseline), partial response (PR) during treatment, and disease progression (PD) after resistance. Through microarray data analysis, five candidate antibodies were screened out for confirmation in serum samples and the verified one was utilized for candidate protein identification through immunoprecipitation-mass spectrometry strategy. A novel protein, isoform 2 of fibrinogen alpha chain (FGA2), was revealed and verified in the discovery sample set. Its performance as therapy indicator was further evaluated in another pre-validation sample set (n = 60). Our data confirmed that serum FGA2 level was correlated with EGFR-TKI response (p < 0.05). The expression and secretion of FGA2 in hepatocytes were inhibited by EGFR-TKI, partially explaining the downregulation of FGA2 in serum. Our results demonstrate that FGA2 is an indicator of targeted therapy for EGFR mutated lung adenocarcinoma. KEY MESSAGES: Antibody microarray was coupled with mass spectrometry for proteomics research. FGA2 was discovered as an indicator of EGFR-TKI targeted therapy. FGA2's expression/secretion in hepatocytes was dramatically inhibited by EGFR-TKI.
Insights
A novel protein, fibrinogen alpha chain isoform 2 (FGA2), has been identified as a therapeutic indicator for EGFR-TKI treatment in lung cancer. Serum FGA2 levels correlate with treatment response, aiding in monitoring therapy effectiveness.
Area of Science:
- Oncology
- Proteomics
- Biomarker Discovery
Background:
- Epidermal growth factor receptor (EGFR) mutations are common in non-small cell lung cancer (NSCLC) and are targeted by EGFR tyrosine kinase inhibitors (TKIs).
- Dynamic monitoring of EGFR-TKI therapy performance is challenging, necessitating the development of reliable therapeutic indicators.
Purpose of the Study:
- To identify novel serum biomarkers for dynamically monitoring the efficacy of EGFR-TKI therapy in EGFR-mutated lung adenocarcinoma.
- To validate the identified biomarker's correlation with treatment response and elucidate its underlying mechanism.
Main Methods:
- Utilized a high-throughput antibody microarray with 41,472 antibodies to analyze serum samples from NSCLC patients and healthy controls at different treatment time points.
- Employed immunoprecipitation-mass spectrometry for protein identification and validated candidate biomarkers in independent patient cohorts.
Main Results:
- Discovered and validated serum isoform 2 of fibrinogen alpha chain (FGA2) as a novel therapeutic indicator.
- Demonstrated a significant correlation between serum FGA2 levels and EGFR-TKI treatment response (p < 0.05).
- Showed that EGFR-TKI inhibits FGA2 expression and secretion in hepatocytes, explaining its downregulation in serum during treatment.
Conclusions:
- Serum FGA2 serves as a promising indicator for monitoring EGFR-TKI targeted therapy in EGFR-mutated lung adenocarcinoma.
- The findings highlight the potential of FGA2 in personalized medicine for NSCLC patients undergoing targeted treatment.
