Prognostic and Therapeutic Significance of DPP4 in SMARCA4-Deficient Non–Small Cell Lung Cancer

Introduction SMARCA4-deficient NSCLC is an aggressive subtype lacking robust biomarkers and therapeutic targets. To define the expression pattern and clinical significance of DPP4 in SMARCA4-dNSCLC and explore whether DPP4 may represent a therapeutic vulnerability in this subtype. Materials and Methods The Cancer Genome Atlas NSCLC cohort was analyzed to compare SMARCA4 -low tumors with adjacent normal lung using differential expression, Cox regression, protein–protein interaction networks, and machine-learning ranking. An exploratory immunohistochemistry case series of SMARCA4-dNSCLC from three centers (n=9) quantified DPP4 by percentage of tumor cells; ≥20% cells defined DPP4-high. Clinicopathologic features, RECIST response, and survival were summarized descriptively by DPP4 status. In HCC827 cells, SMARCA4 knockdown and DPP4 inhibition (P32/98) were evaluated alone and in combination using colony-formation, and motility (migration/wound-healing) assays. Results DPP4 was downregulated in SMARCA4 -low tumors versus adjacent normal lung, yet within tumors higher residual DPP4 expression was associated with worse overall and disease-free survival. In the immunohistochemistry case series, DPP4 protein expression was weaker in SMARCA4-dNSCLC than in adjacent alveolar epithelium. Within this low-expressing background, DPP4-high tumors showed descriptive trends toward inferior survival, lower disease-control rate after first-line therapy, and more extensive baseline organ involvement than DPP4-low tumors. In vitro, SMARCA4 knockdown and P32/98 each reduced clonogenic growth and motility versus control, with the combination producing the greatest inhibition (about 60%–70% reductions). Conclusions DPP4 is downregulated at the mRNA and protein levels in SMARCA4-dNSCLC compared with normal lung, yet higher residual expression may mark a more aggressive phenotype. Combined SMARCA4 knockdown and DPP4 inhibition suppress growth and motility in vitro, suggesting DPP4 as a candidate prognostic marker and a candidate therapeutic target that requires orthogonal specificity controls and validation in larger cohorts.