c-MET Overexpression Drives AKT Activation, and Combined Inhibition Synergistically Enhances Therapeutic Sensitivity in Non-Small-Cell Lung Cancer

Aberrant activation of c-MET signaling contributes to tumor progression and resistance to therapy in non-small-cell lung cancer (NSCLC), yet its therapeutic significance remains incompletely understood. In this study, we evaluated c-MET expression and its association with AKT activation and clinical outcomes using a tissue microarray cohort and publicly available datasets. c-MET overexpression was significantly associated with increased p-AKT expression and showed a trend toward poorer overall survival in the tissue microarray cohort, while analysis of the TCGA LUAD dataset confirmed a significant association with reduced survival (log-rank p = 0.0223; HR = 1.234, 95% CI: 1.029–1.480). Functional studies demonstrated that pharmacological inhibition of c-MET suppressed cell proliferation and induced caspase-dependent mitochondrial apoptosis in NSCLC cell lines. Mechanistically, c-MET inhibition resulted in AKT inactivation, identifying AKT as a key downstream mediator of c-MET signaling. Notably, combined inhibition of c-MET (PHA665752) and AKT (MK2206) exhibited strong synergistic effects, significantly enhancing apoptosis and reducing cell viability compared to single-agent treatments. These findings were further validated in vivo, where combination therapy markedly delayed tumor growth without significant toxicity. Collectively, our results highlight c-MET-driven AKT activation as a key oncogenic mechanism and support dual c-MET/AKT targeting as a promising therapeutic strategy for NSCLC.