Abstract 2245 Discovery and functional characterization of potential biomarkers for wild-type EGFR lung adenocarcinoma via super-SILAC-based quantitative tissue proteomic analysis

Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancers, and adenocarcinoma (LUAD) is the most common subtype of NSCLC. Epidermal growth factor receptor (EGFR) mutations are common in LUAD patients (∼60%) from East Asian countries, especially nonsmoking women in Taiwan. EGFR tyrosine kinase inhibitors have been developed to benefit LUAD patients harboring EGFR-activating mutation (MT); unfortunately, biomarkers for early diagnosis and targeted therapy in EGFR-wild-type (WT) patients are currently lacking. Based on super-SILAC, we established a LUAD proteomics dataset related to stage and EGFR status, representing one of the few studies focusing on EGFR-WT LUAD patients. For clinical practice, we focused on validating marker candidates enriched in EGFR-WT and located in the plasma membrane or extracellular space. Dysregulation of myeloid-derived growth factor (MYDGF), a promising marker candidate, was validated by immunohistochemistry and ELISA. High expression of tissue MYDGF correlated positively with good prognosis in patients with EGFR-WT but not EGFR-MT. Unexpectedly, serum levels of MYDGF in early-stage EGFR-WT LUAD were significantly lower than those in healthy controls and late-stage LUAD, suggesting that lower serum MYDGF might serve as a potential marker specific for early-stage EGFR-WT LUAD. Three MYDGF constructs with full-length WT, secretion-deficient, and secretion-preferred fragments were generated to explore the differential functions of intracellular and extracellular MYDGF in LUAD cells. Notably, we observed that secreted MYDGF promoted the proliferation and migration ability of EGFR-WT LUAD cells, whereas secretion-deficient MYDGF showed the opposite effect. Together, our results provide new insights into LUAD diagnosis/prognosis of EGFR-WT and support a dual role for MYDGF in LUAD cancer development. This work was financially supported by grants from the National Science and Technology Council, Taiwan (108-2320-B-182-007-MY3 and 111-2320-B-182-019-MY3 to CJ Yu); the Chang Gung Memorial Hospital, Taoyuan, Taiwan (CMRPD1M0441-2 and BMRP894 to CJ Yu); and the Molecular Medicine Research Center, Chang Gung University from the Ministry of Education, Taiwan.