Discovery of survival predictor and early monitoring biomarkers for EGFR tyrosine kinase inhibitor therapy in lung adenocarcinoma by integrative omics analysis

Abstract

Epidermal growth factor receptor (EGFR) mutation is a predictor of the initial treatment efficacy of tyrosine kinase inhibitors (TKIs) in advanced lung adenocarcinoma (ADC). Unfortunately, neither EGFR mutations nor molecular markers can accurately monitor cancer progression or predict patient survival. EGFR‐TKI susceptibility‐associated biomarkers to benefit lung ADC patients are in high demand. Plural effusion (PE) has been recognized as a promising source for biomarker discovery. By integrating PE proteomic and tissue genomic analyses, we herein identified fifteen proteins as potential biomarkers of EGFR‐TKI resistance. Among these candidates, cadherin‐3 (CDH3) attracted our attention, as we observed that the CDH3 protein expression level was indeed positively correlated with malignancy as well as EGFR‐TKI resistance in our verified cancerous tissues, PEs and cell lines. Importantly, altered soluble CDH3 (sCDH3) levels in the serum could be used to monitor the efficacy of EGFR‐TKIs at one month after treatment. Furthermore, the baseline serum sCDH3 level was associated with progression‐free survival in ADC patients with mutant but not wild‐type EGFR. Finally, we observed that the baseline serum sCDH3 level was positively associated with tumor stage and overall survival in advanced non‐small cell lung cancer patients. Our results collectively establish a biomarker dataset for EGFR‐TKI resistance and sCDH3 is identified as a survival predictor and real‐time indicator of treatment efficacy in ADC patients received EGFR‐TKI therapy.Support or Funding InformationMinistry of Science and Technology, Taiwan, R.O.C. (108‐2320‐B‐182‐007‐MY3) and Chang Gung Medical Research Fund (CORPD1J0091, CMRPD1H0081‐3, CMRPD1H0641‐2, CMRPD1H0082 and BMRP894).