ABSTRACT: Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is a highly effective and valuable treatment option for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations, like T790M. However, acquired resistance ultimately limits its clinical application. In this study, we constructed H1975/OSI cell lines and utilized potentially complementary transcriptomic and proteomic techniques, which may provide insight into the intricately complex molecular mechanisms, to reveal potential therapeutic targets associated with Osimertinib resistance. Uni-omics and multi-omics analyses were conducted on the transcriptomic and proteomic (4D label-free) expression profiles, which involved differential expression analysis, GO functional annotation and KEGG pathway enrichment analysis, correlation analysis of transcription factors, PPI network and Cytoscape analysis. We highlighted multiple signaling pathways and eleven hub-genes, including NOP56, DDX21, PDCD11, CCNB1, TOP21, KPNA2, DDX5, EFTUD2, BRCA1, LMNB1 and HIF1A, that may be the key to overcoming resistance. Further validation of these targets and molecules in preclinical and clinical studies could lead to the development of new and more effective treatment options for H1975-resistant patients.
