C1orf116 inhibits acquired resistance to EGFR inhibitors in EGFR mutant lung adenocarcinoma by suppressing the ATM/ATR pathways.

Background: In patients with lung adenocarcinoma (LUAD) who harbor activating mutations in the epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors (TKIs) are frequently employed as a therapeutic strategy. However, despite an initial favorable response to these EGFR-TKIs, a significant number of patients eventually acquire resistance over time, thereby reducing the efficacy of the treatment. The aim of this study is to explore the role of C1orf116 in the development of acquired resistance to erlotinib in LUAD. Methods: We identified differentially expressed genes (DEGs) between HCC827 cells and their erlotinib-resistant counterparts, HCC827/ER cells, using data from GSE69181 and GSE121634. Notably, C1orf116 exhibited significant downregulation in the HCC827/ER cells. The erlotinib-resistant HCC827/ER cells were established by progressively increasing the concentration of erlotinib in the initially sensitive HCC827 cells. We then transfected HCC827/ER cells with C1orf116 to examine Cell Counting Kit-8 (CCK-8) assays, transwell assays, wound healing assays, flow cytometry, and subcutaneous tumor models in nude mice, both Results: The expression of C1orf116 was significantly reduced in HCC827/ER cells. Prognostic analysis found that low C1orf116 correlated with reduced overall survival. Upregulation of C1orf116 inhibited proliferation, invasion and migration of HCC827/ER cells. Further, overexpression of C1orf116 increased sensitivity to erlotinib for HCC827/ER cells Conclusions: Low expression of C1orf116 enhances the DNA damage response and promotes resistance to EGFR inhibitors in LUAD. This discovery suggests a potential therapeutic approach to combat acquired resistance through targeting the ATM/ATR signaling pathway.