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

Introduction: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) benefit advanced lung adenocarcinoma (ADC) patients 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. Methods: We applied quantitative proteomics to generate the TKI resistance-associated pleural effusion (PE) proteome from ADC patients 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 enzyme-linked immunosorbent assays (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 to 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 one month of treatment (n=43). Baseline sCDH3 was significantly associated with PFS and OS in ADC patients after EGFR-TKI therapy (n=76). Moreover, sCDH3 was positively associated with tumor stage in non-small cell lung cancer (NSCLC) (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 ADC patients treated with EGFR-TKIs.