Background This study investigates the relationship between the expression level of Yes-associated protein (YAP) in pretreatment cancer and adjacent non-cancerous tissues of patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) who progressed after first-line EGFR-tyrosine kinase inhibitor (TKI) treatment, as well as its correlation with clinicopathological characteristics and prognosis.

Methods We retrospectively collected data on 80 patients with EGFR-mutant NSCLC who progressed after first-line EGFR-TKI treatment and were admitted to Zhejiang Provincial People’s Hospital and Jinling Hospital, Medical School of Nanjing University from August 1, 2015, to October 1, 2025. Using pretreatment surgical or biopsy specimens, immunohistochemistry was used to detect the expression of YAP in cancer and paired adjacent non-cancerous tissues from the patients, and the correlation between its expression level and clinical characteristics was analyzed. Kaplan-Meier method was used for survival analysis, and Cox proportional hazards model was used for prognostic factor analysis with EGFR-TKI generation included as a covariate in sensitivity analysis.

Results The high expression rate of YAP in cancer tissues (82.5%, 66/80) was significantly higher than that in adjacent non-cancerous tissues and normal tissues (both P<0.05). The expression level of YAP was significantly correlated with extrathoracic metastasis, neural invasion, vascular invasion, lymph node metastasis, and TNM staging of the tumor (all P<0.05). Survival analysis showed that the overall survival (OS) of the high YAP expression group was statistically different from that of the low expression group (P=0.032). Univariate Cox analysis indicated that YAP high expression was a poor prognostic factor for OS hazard ratio (HR)=2.155, P=0.032. Multivariate analysis showed that lymph node metastasis (HR=3.021, P=0.027), TNM staging (HR=3.331, P=0.002) and TKI generation (third-generation vs. first/second-generation, HR=0.556, P=0.015) were independent prognostic factors for OS, while YAP did not enter the final model (HR=1.519, 95% confidence interval 0.71~3.28, P=0.286). Collinearity diagnosis confirmed that there was no severe multicollinearity among key variables, with all variance inflation factors (VIF) <2. YAP expression level was not significantly correlated with TKI generation selection (P>0.05), excluding the possibility of YAP as a confounding factor for treatment selection.

Conclusion YAP is commonly overexpressed in pretreatment cancer tissues of EGFR-mutant NSCLC patients and is associated with tumor aggressive characteristics and poor prognosis after subsequent EGFR-TKI treatment. Multivariate analysis indicates that YAP is not an independent prognostic factor, suggesting that prognostic information related to YAP may be obscured by clinical characteristics such as TNM staging and TKI generation.