CKAP4 is a potential therapeutic target to overcome resistance to EGFR-TKIs in lung adenocarcinoma.

Background: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard treatments for non-small cell lung cancer (NSCLC) patients with EGFR mutations; however, drug resistance limits their efficacy. Cytoskeleton-associated protein 4 (CKAP4) has been linked to cancer progression, but its role in EGFR-TKI resistance remains unclear.

Objective: This study investigates the clinical relevance of CKAP4 as a therapeutic target to overcome EGFR-TKI resistance in lung adenocarcinoma (LUAD) patients.

Methods: GEO datasets were analyzed to identify 24 differentially expressed genes associated with EGFR-TKI resistance, with CKAP4 selected via functional annotation and scoring using the VarElect tool. The prognostic significance of CKAP4 was evaluated using public databases, and its upregulation was confirmed in osimertinib-tolerant H1975 cells through quantitative reverse transcription-polymerase chain reaction.

Results: Integrated bioinformatics analysis identified CKAP4 as strongly associated with EGFR-TKI resistance. Elevated CKAP4 expression was particularly linked to poorer clinical outcomes in LUAD patients. Notably, osimertinib-tolerant cells exhibited high CKAP4 expression, correlating positively with increased half-maximal inhibitory concentrations of EGFR-TKIs. LUAD patients with upregulated CKAP4 showed significantly reduced overall and relapse-free survival.

Conclusion: This study underscores the prognostic value of CKAP4 in EGFR-mutated LUAD and highlights its potential as a therapeutic target to counter EGFR-TKI resistance.