Integrative Omics Analysis Reveals Soluble Cadherin-3 as a Survival Predictor and an Early Monitoring Marker of EGFR Tyrosine Kinase Inhibitor Therapy in Lung Cancer
| Autor: | Hao-Yu Lin, Jau-Song Yu, Chia-Jung Yu, Ko-Jiunn Liu, Ting-Feng Hsiao, Hsiang-Pu Feng, Gee-Chen Chang, Yi-Cheng Wu, Yen-Chuan Chiu, Kun-Yi Chien, Chih-Liang Wang |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Proteomics 0301 basic medicine Cancer Research Lung Neoplasms Quantitative proteomics Drug resistance 03 medical and health sciences 0302 clinical medicine Tandem Mass Spectrometry Cell Line Tumor Biomarkers Tumor Humans Medicine Molecular Targeted Therapy Lung cancer Protein Kinase Inhibitors Neoplasm Staging Gene knockdown business.industry Cadherin Cadherins Prognosis EGFR Tyrosine Kinase Inhibitor Therapy medicine.disease Omics respiratory tract diseases ErbB Receptors Treatment Outcome 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Adenocarcinoma Female business Chromatography Liquid |
| Zdroj: | Clinical Cancer Research. 26:3220-3229 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-19-3972 |
| Popis: | Purpose: EGFR tyrosine kinase inhibitors (EGFR-TKI) benefit patients with advanced lung adenocarcinoma (ADC) harboring activating EGFR mutations. We aimed to identify biomarkers to monitor and predict the progression of patients receiving EGFR-TKIs via a comprehensive omic analysis. Experimental Design: We applied quantitative proteomics to generate the TKI resistance–associated pleural effusion (PE) proteome from patients with ADC with or without EGFR-TKI resistance. Candidates were selected from integrated genomic and proteomic datasets. The PE (n = 33) and serum (n = 329) levels of potential biomarkers were validated with ELISAs. Western blotting was applied to detect protein expression in tissues, PEs, and a cell line. Gene knockdown, TKI treatment, and proliferation assays were used to determine EGFR-TKI sensitivity. Progression-free survival (PFS) and overall survival (OS) were assessed to evaluate the prognostic values of the potential biomarkers. Results: Fifteen proteins were identified as potential biomarkers of EGFR-TKI resistance. Cadherin-3 (CDH3) was overexpressed in ADC tissues compared with normal tissues. CDH3 knockdown enhanced EGFR-TKI sensitivity in ADC cells. The PE level of soluble CDH3 (sCDH3) was increased in patients with resistance. The altered sCDH3 serum level reflected the efficacy of EGFR-TKI after 1 month of treatment (n = 43). Baseline sCDH3 was significantly associated with PFS and OS in patients with ADC after EGFR-TKI therapy (n = 76). Moreover, sCDH3 was positively associated with tumor stage in non–small cell lung cancer (n = 272). Conclusions: We provide useful marker candidates for drug resistance studies. sCDH3 is a survival predictor and real-time indicator of treatment efficacy in patients with ADC treated with EGFR-TKIs. |
| Databáze: | OpenAIRE |
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