RBM15 plays a key driving role in the tumorigenesis of EGFR-mutant lung adenocarcinoma and gefitinib resistance.

Abstract

EGFR is a key oncogenic driver of lung adenocarcinoma, and resistance to its tyrosine kinase inhibitors has become a major clinical challenge in the treatment of EGFR-mutated LUAD patients. Through preliminary experiments including Western blot and immunohistochemistry staining, RBM15 was identified as an oncogene promoting drug resistance in EGFR-mutant LUAD cell lines PC-9 and HCC827. Analysis of the TCGA-LUAD cohort revealed a positive correlation between RBM15 and EGFR expression, whereas RBM15 gain-of-function was negatively associated with LUAD patient survival. RBM15 expression was higher in EGFR-mutant LUAD cell lines PC-9 and HCC827 compared to non-EGFR-mutant cell line A549. Furthermore, RBM15 was downregulated in PC-9 and HCC827 cells following gefitinib treatment. Knockdown of RBM15 reduced proliferation and promoted apoptosis in PC-9 and HCC827 cells in vitro, while also inhibiting the growth of PC-9 xenograft tumors in mice. Notably, RBM15 overexpression rescued these effects and promoted gefitinib resistance in PC-9 and HCC827 cells. Transcriptomic and metabolomic sequencing analyses of RBM15-knockdown PC-9 cells revealed enrichment in multiple cancer signaling pathways, including mitochondrial fatty acid metabolism. Diacylglycerol kinase ε (DGKE) was identified as a novel interacting protein of RBM15, and RBM15 was found to influence fatty acid metabolism by modulating mitochondrial function. In summary, RBM15 promotes tumorigenic proliferation, suppresses apoptosis, and enhances gefitinib resistance in EGFR-mutant LUAD cells by regulating the EGFR signaling pathway and interacting with DGKE. Based on the interplay among RBM15, EGFR, and downstream DGKE, RBM15 may serve as a promising new therapeutic target for EGFR-mutant LUAD.