Exploratory multiomics analysis identifies WDR17 as a potential biomarker of tyrosine kinase inhibitor resistance in lung adenocarcinoma.

objectiveDrug resistance remains a major clinical challenge in advanced lung adenocarcinoma. Identifying commonly dysregulated resistance-associated genes may provide mechanistic insights for novel therapeutic strategies.

methodsRNA-seq data from eight TCGA LUAD patients with documented TKI treatment were analyzed using the limma empirical Bayes framework for exploratory differential expression analysis. WDR17 association with clinicopathological features was evaluated in the TCGA cohort. Single-cell transcriptomics from publicly available datasets (GSE139386 and GSE260499) was used to characterize WDR17 distribution in TKI-resistant cell lines. In vitro experiments assessed the functional relevance of WDR17 in drug sensitivity.

resultsExploratory differential expression analysis identified WDR17 as significantly downregulated in the non-responding group (log2 FC =  - 1.11, adjusted P = 0.026). In the broader TCGA-LUAD cohort, high WDR17 expression was associated with longer overall survival (HR = 0.78, 95% CI: 0.67-0.91, P < 0.001). Single-cell analysis revealed that WDR17 was predominantly expressed in a cell state characterized by protein homeostasis and metabolic stress. Computational estimation using the EPIC algorithm suggested a positive correlation between WDR17 expression and CD8 + T-cell infiltration (P < 0.05). In vitro experiments confirmed that WDR17 overexpression enhanced crizotinib sensitivity in resistant cells, whereas knockdown reduced sensitivity in parental cells.

conclusionThis exploratory study identified WDR17 as a candidate biomarker associated with TKI resistance in lung adenocarcinoma, potentially involved in maintaining protein homeostasis and metabolic balance. These preliminary findings warrant validation in larger, independent cohorts.