This study aimed to determine the molecular markers related to gefitinib sensitivity for guiding the prognosis of lung adenocarcinoma (LUAD) and providing new evidence for promoting the precise treatment of LUAD.Lung adenocarcinoma (LUAD) is a prevalent lung cancer subtype with inferior survival outcomes. However, gefitinib is the first molecular targeted drug approved by Food and Drug Administration (FDA) to treat advanced LUAD. Gefitinib sensitivity-related gene targets for LUAD are rarely studied.This study was designed to probe the potential molecular markers related to the sensitivity of gefitinib in LUAD.The gene expression profiles of LUAD cells in the Genomics of Drug Sensitivity in Cancer (GDSC) database were used for Weighted Gene Co-expression Network Analysis (WGCNA) to select the modules most related to gefitinib sensitivity. The Cancer Genome Atlas (TCGA) database was used to compare the expression of LUAD and para-cancerous tissues. Differentially expressed genes (DEGs) were then filtered and intersected with the highly linked genes in the module relevant to gefitinib sensitivity. Univariate Cox regression analysis was conducted to identify prognostically related genes to LUAD. The correlation between genes and drug IC50 was calculated by Spearman correlation analysis. Quantitative RT-PCR and immunofluorescence detection validated hub genes FAM13B and PFKP expressions.Among the 10 modules divided by WGCNA, the module with the most significant positive correlation and the most significant negative correlation with gefitinib sensitivity were found. FAM13B, PFKP, FGD3, RNASE1, MUC16, GJB5, and GJB3 were hub genes related to gefitinib sensitivity in LUAD. Significantly, the low expressed FAM13 in LUAD tissues positively correlated with immune response. At the same time, overexpressed PFKP in the LUAD cohort was related to an unfavorable prognosis, cell proliferation, and cell cycle. We also found that FAM13B and PFKP expressions were enhanced in LUAD cell lines.This study identified 7 critical genes related to gefitinib sensitivity in LUAD. Functionally, genes positively correlated with gefitinib sensitivity might regulate the progression of LUAD through the immune, cell cycle, and metabolic pathways and showed potential effects in predicting sensitivity to different drugs. These findings help offer a theoretical direction for personalized treatment of LUAD.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.