Targeting the BRD4/FOXO3a/CDK6 axis sensitizes AKT inhibition in luminal breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Bromodomain and extra-terminal domain (BET) proteins, like BRD4, regulate gene transcription crucial for cancer progression.
• The role of BRD4 in the development of drug resistance in cancer remains largely unexplored.
• AKT inhibitors are a therapeutic strategy for breast cancer, but resistance can develop.

Purpose of the Study:

• To investigate the involvement of BRD4 in acquired resistance to AKT inhibitors in luminal breast cancer.
• To elucidate the molecular mechanisms underlying BRD4-mediated drug resistance.

Main Methods:

• Prolonged treatment of luminal breast cancer cells with AKT inhibitors.
• Analysis of FOXO3a phosphorylation, nuclear translocation, and interactions with SirT6 and BRD4.
• Assessment of BRD4/FOXO3a complex recruitment to the CDK6 promoter.
• Pharmacological inhibition of BRD4/FOXO3a association and CDK6.
• In vitro and in vivo studies to evaluate drug resistance reversal.

Main Results:

• AKT inhibitor treatment induced FOXO3a dephosphorylation, nuclear translocation, and dissociation from SirT6.
• FOXO3a became acetylated, enabling recognition by BRD4.
• Acetylated FOXO3a recruited the BRD4/RNA Polymerase II complex to the CDK6 promoter, driving its transcription.
• Inhibition of BRD4/FOXO3a interaction or CDK6 restored sensitivity to AKT inhibitors.

Conclusions:

• The BRD4/FOXO3a/CDK6 axis is a key mechanism driving resistance to AKT inhibitors in luminal breast cancer.
• Targeting the BRD4/FOXO3a interaction or CDK6 represents a promising therapeutic strategy to overcome AKT inhibitor resistance.