Inhibition of CDK4/6 and BET suppresses pancreatic tumor growth and epithelial-to-mesenchymal transition independently of PI3K-AKT by regulating phosphorylation of GSK3β induced Wnt/β-catenin pathway

Abstract

Abstract The cyclin-dependent kinases, CDK4 and CDK6 are upregulated in various cancers, including pancreatic ductal adenocarcinoma. However, monotherapy with CDK4/6 inhibitors has been unsatisfactory and several oncogenic pathways might be activated. We demonstrated that PD-0332991, an FDA-approved CDK4/6 inhibitor, moderately suppressed tumor growth and induced the epithelial-to-mesenchymal transition (EMT). However, the performance of this inhibitor was significantly improved and the EMT partly reversed when bromodomain and extra-terminal motif (BET) was inhibited by JQ1. Mechanistically, CDK4/6 inhibition activated the canonical Wnt/β-catenin pathway through GSK3β Ser9 phosphorylation. Crosstalk between the TGFβ/Smad and Wnt/β-catenin pathways based on GSK3β was disrupted by JQ1 and levels of active β-catenin were suppressed by regulating the phosphorylation status of GSK3β. The simultaneous inhibition of CDK4/6 and BET synergistically suppressed tumor growth in vitro and in vivo. Moreover, CDK4 and CDK6 negatively correlated with overall survival, and the predictive accuracy of a CDK4/6-based nomogram was higher than that of tumor size, nodes, and metastasis (TNM) classification alone. Our findings provide theoretical evidence for the construction of predictive models and new targets with which to treat pancreatic cancer.