This study aimed to generate Car- and Pac-resistant cell lines from the human lung adenocarcinoma H1792 cell line, designated as H1792/Car and H1792/Pac, and perform transcriptome sequencing to identify potential targets. Common differentially expressed genes (Co-DEGs) in both resistant cell lines were identified, followed by hub gene identification. Online validation was conducted through GEPIA and Kaplan–Meier Plotter platforms, with experimental validation performed using real-time quantitative PCR (RT-qPCR). After six months, the H1792/Car and H1792/Pac cell lines exhibited a 10.7-fold and 5.6-fold increase in resistance to Car and Pac, respectively. Flow cytometry analysis demonstrated that both resistant cell lines were resistant to cell cycle arrest and apoptosis induced by Car or Pac. Transcriptomic sequencing identified 123 Co-DEGs, including 72 upregulated and 51 downregulated genes, consistently expressed in both H1792/Car and H1792/Pac cell lines. Among these, 13 hub genes were identified, with colony-stimulating factor 3 (CSF3) uniquely associated with post-progression survival (PPS) in adenocarcinoma patients undergoing chemotherapy. Notably, CSF3 expression was significantly elevated in both H1792/Car and H1792/Pac compared to parental cells. These findings underscore the value of drug-resistant models in uncovering critical biomarkers. CSF3 emerges as a promising guiding marker or potential molecular target for optimizing Car- and Pac-based doublet regimens.

Erlotinib (ER) and gefitinib (GB) are frequently prescribed for patients with advanced lung adenocarcinoma (ADC). Although both ER and GB significantly extend median survival, several patients experience early disease relapse due to treatment resistance. This study aimed to identify common genes associated with acquired resistance to ER or GB. This integrative analysis of transcriptomic data identified differentially expressed genes by comparing sensitive PC-9 cells with ER-resistant (PC-9/ER) or GB-resistant (PC-9/GB) cell lines. A Venn diagram was used to identify common genes. Candidate genes were confirmed in our generated drug-resistant cell lines. After six months, the PC-9/ER and PC-9/GB cell lines exhibited 40.7-fold and 109.2-fold increases in resistance to ER and GB, respectively. Flow cytometric analysis demonstrated that both resistant cell lines were resistant to cell cycle arrest and apoptosis induced by ER or GB. Through integrated analysis, we found that two genes, KRT13 and CEACAM5, were up-regulated in both the PC-9/ER and PC-9/GB cell lines. The expression patterns of these two genes did not align with the transcriptome, with only CEACAM5 exhibiting consistent gene and protein expressions. Our findings indicate that CEACAM5 serves as a biomarker for predicting the response of patients to ER and GB treatments.