Targeting CDK1 suppresses non-small cell lung cancer progression by regulating the β-catenin/MEK-ERK signaling pathway

Non-small cell lung Cancer (NSCLC) remains a leading cause of cancer-related mortality, largely driven by late-stage diagnosis and complex, multi-pathway signaling resistance. Here, we identify Cyclin-dependent kinase 1 (CDK1) as a critical oncoprotein and master regulator of NSCLC progression. Clinical analysis reveals that elevated CDK1 expression in patient tumors strongly correlates with advanced pathological stage, lymph node metastasis, and poor overall survival. Through bidirectional functional assays and cell-derived xenograft (CDX) models, we demonstrate that CDK1 is both necessary and sufficient to drive NSCLC proliferation and macroscopic tumor expansion in vivo. Mechanistically, CDK1 promotes tumorigenesis by establishing an epistatic dependency on the MYC oncogene, wherein MYC upregulation is strictly required for CDK1-induced clonogenic survival. Furthermore, utilizing highly translational patient-derived xenograft (PDX) models, we show that targeted genetic ablation or pharmacological inhibition of CDK1 (via NU6102) profoundly suppresses tumor growth. This therapeutic efficacy is achieved by dismantling a broader oncogenic network, simultaneously uncoupling the Wnt/β-catenin and MAPK/ERK signaling cascades alongside MYC. Collectively, our findings redefine CDK1 from a canonical cell cycle checkpoint regulator to a targetable upstream master kinase in NSCLC, providing a compelling preclinical rationale for integrating CDK1-directed interventions to combat advanced, aggressively disseminating disease.