FAK Inhibition Demonstrates Dual Effects of Tumor Suppression and Dormancy Induction Through Region-Specific COUP-TF1 Regulation

Background Although focal adhesion kinase (FAK) inhibition shows promise in lung cancer therapy, emerging evidence suggests it may promote cellular dormancy and drug resistance through transcriptional regulation. We investigated the therapeutic efficacy and drug resistance inhibition mechanisms of FAK inhibitor VS-4718 in lung cancer. Methods Using an orthotopic syngeneic LLC1 mouse model, we evaluated the effects of VS-4718 (50 mg/kg/day) on tumor progression, survival, and molecular mechanisms. Comprehensive analyses included histological examination, immunohistochemistry, Western blotting, and clinical tissue validation from TKI-treated patients. Results VS-4718 demonstrated significant anti-tumor efficacy, reducing tumor burden by 60%, decreasing surface nodules, and improving overall survival (p < 0.01). Mechanistically, FAK inhibition induced cell cycle arrest through spatially heterogeneous p27 upregulation at tumor margins while suppressing Cyclin A1 expression. Unexpectedly, VS-4718 controlled COUP-TF1/β-catenin interactions, leading to reciprocal protein regulation. Critically, region-specific analysis revealed selective COUP-TF1 upregulation in bronchiolar areas, indicating anatomically-restricted dormancy pathway activation. Clinical validation in TKI-treated patient samples confirmed variable COUP-TF1 expression patterns, supporting its potential as a therapeutic resistance biomarker. Conclusions VS-4718 achieved significant therapeutic benefits through coordinated regulation of cell cycle and transcriptional networks. However, concurrent induction of COUP-TF1-mediated dormancy pathways, particularly in bronchiolar niches, may promote the formation of therapy-resistant cell populations. These findings reveal a fundamental paradox in FAK-targeted therapy and suggest that monotherapy may be insufficient for complete tumor eradication. Our