# CDK4/6 and BET inhibitors synergistically suppress pancreatic tumor growth and epithelial-to-mesenchymal transition by regulating the GSK3β-mediated Wnt/β-catenin pathway

## TL;DR

Combining CDK4/6 and BET inhibitors effectively stops pancreatic tumor growth and reduces cancer cell spread by targeting key signaling pathways.

## Contribution

A novel combination therapy using CDK4/6 and BET inhibitors to synergistically suppress pancreatic cancer progression.

## Key findings

- Palbociclib alone promotes tumor cell migration and EMT despite inhibiting tumor growth.
- JQ1 reverses EMT and enhances palbociclib's anti-proliferative effects when used in combination.
- The combination therapy disrupts Wnt/β-catenin and TGF-β/Smad signaling pathways synergistically.

## Abstract

Aim: Cyclin-dependent kinases 4 and 6 (CDK4/6) are frequently upregulated in pancreatic ductal adenocarcinoma (PDAC) and are associated with poor overall survival. Although CDK4/6 inhibition suppresses tumor cell proliferation, it paradoxically promotes metastasis and invasion, and the mechanisms underlying this effect remain unclear.

Methods: We evaluated the effects of the CDK4/6 inhibitor palbociclib (PD-0332991) and the bromodomain and extra-terminal (BET) inhibitor JQ1, administered individually and in combination, on human PDAC cell lines in vitro and on tumor growth in an orthotopic mouse model.

Results: Palbociclib modestly inhibited pancreatic tumor growth but significantly enhanced tumor cell migration, invasion, and epithelial-to-mesenchymal transition (EMT). In contrast, co-treatment with JQ1 potentiated palbociclib’s anti-proliferative effects and reversed EMT. Mechanistically, CDK4/6 inhibition activated the canonical Wnt/β-catenin pathway via Ser9 phosphorylation of GSK3β, whereas BET inhibition disrupted the cross-talk between Wnt/β-catenin and TGF-β/Smad signaling. Combined inhibition of CDK4/6 and BET produced a synergistic antitumor effect in vitro and in vivo.

Conclusion: Our findings support a combined therapeutic strategy targeting CDK4/6 and BET proteins to achieve synergistic inhibition of PDAC progression.