Exploring the characteristics of the SKP2-CDK6 axis in pancreatic cancer cell metastasis and its clinical significance

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic malignancy with limited biomarkers for early detection. Recurrence and metastasis after surgical resection remain major causes of mortality, highlighting the urgent need for novel therapeutic strategies. We integrated clinical database analyses and functional assays in PDAC cell lines and mouse models to investigate the role of the SKP2-CDK6 axis in tumor progression, metastasis, and gemcitabine resistance. Elevated CDK6 expression correlated with poorer progression-free and overall survival in PDAC patients and was associated with advanced stage and lymph node metastasis. SKP2 expression positively correlated with CDK6, and mechanistic studies revealed that SKP2 may transcriptionally regulate CDK6. Inhibition of CDK6 suppressed tumor growth and metastasis in vitro and in vivo, and reduced epithelial-mesenchymal transition. Combining a CDK6 inhibitor with gemcitabine significantly reduced colony formation in gemcitabine-resistant PDAC cells, suggesting a synergistic anticancer effect. The SKP2-CDK6 axis may drive PDAC progression and chemoresistance. Co-targeting SKP2 and CDK6 in combination with gemcitabine may represent a promising therapeutic approach, warranting further preclinical and clinical evaluation to improve outcomes for patients with PDAC. • Inhibition or knockdown of CDK6 significantly suppressed tumor growth and metastasis in PDAC models. • Elevated CDK6 expression is linked to poor clinical outcomes and contributes to gemcitabine resistance in PDAC cells. • Combined targeting of the SKP2-CDK6 axis with gemcitabine synergistically enhanced cytotoxicity and overcame drug resistance.