Introduction: Lung adenocarcinoma (ADC) is the most common subtype of non-small cell lung cancer. Epidermal growth factor receptor (EGFR) mutation is a predictor for initial treatment efficacy of inhibitors (EGFR-TKIs). Unfortunately, it can’t be used to evaluate the outcomes of cancer patients. In addition, the drug-resistance against EGFR-TKIs and the following chemotherapy eventually lead to the poor survival of cancer patients. It is therefore important to search the drug susceptibility-associated biomarkers to benefit lung ADC patients. Pleural effusion (PE), a tumor-proximal body fluid, is associated with lung malignancy and serves as a promising source for biomarker discovery.
Methods: We herein applied high-abundant serum protein removal system and iTRAQ-based quantitative proteomics approach to generate the drug resistance-associated PE proteome with 561 quantified proteins from lung ADC patients who were sensitive or resistant to EGFR-TKI, EGFR-TKI/chemotherapy, and benign pulmonary disease. Both of the PE and serum levels of potential biomarkers were verified by ELISA. The protein expression in lung tissues was detected by Western blotting. Progression free survival (PFS) and overall survival (OS) were included to evaluate the prognostic value of potential maker.
Results: We selected seven proteins as potential markers of EGFR-TKI resistance by integration of our PE proteome with Gene Expression Profilling Interactive Analysis. We confirmed that the PE level of CDH3 was increased in patient with EGFR-TKI resistance as compared to patients with treatment naïve. The protein level of CDH3 was significantly increased in lung ADC tissue compared to adjacent normal parts. The serum level of CDH3 was indeed correlated to treatment efficacy of EGFR-TKI. Importantly, the CDH3 levels at baseline were associated with PFS and OS of ADC patients.
Conclusions: Our results collectively provide the useful databases for drug resistance study and prognosis of advanced ADC patients with targeted therapy.