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Lung cancer remains the leading cause of cancer-related mortality worldwide. The identifica on of the epidermal growth factor receptor (EGFR) driver mutation has expanded therapeutic strategies; nonetheless, challenges such as drug resistance and distant metastasis persist. Our recent efforts have focused on developing novel diagnostic and therapeutic targets using advanced proteomic techniques. Notably, phosphoproteomic analyses identified HMGA1, a CK2 substrate, as a novel target associated with drug resistance in non-small cell lung cancer (NSCLC). Addi onally, our studies of the EGFR interactome indicate that gefitinibtreated lung cancer cells may alter EGFR recycling via Rab7 ubiquitination, thereby promoting autophagy and contributing to resistance mechanisms. Through phenotypic screening combined with chemical proteomics, we identified three small molecules—GRC0321, AS7128, and AS4583—as potential therapeutics. Structure-activity relationship (SAR) studies and intisilico modeling refined GRC0321 from an initial hit to a lead compound. Furthermore, membrane- and total-proteomic analyses highlighted the critical roles of GPNMB and LCRMP1 in lung cancer metastasis and angiogenesis. Lastly, we developed a GPNMB-specific protein chip suitable for clinical applica on. 

Keywords:  NSCLC, EGFR-TKI drug resistance, metastasis, proteomic analyses, and phenotypic drug screening.