Targeting PRKCN, an Essential Driver Orchestrating mTOR-IRF4 Axis Independently of Kinase Activity, in Multiple...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Multiple myeloma (MM) is an incurable plasma cell malignancy.
• Deregulated Protein Kinase N (PKN) C is implicated in solid tumors, but its role in MM is unclear.
• Novel therapeutic targets are crucial for overcoming MM's incurability and drug resistance.

Purpose of the Study:

• To investigate the role of PRKCN in multiple myeloma.
• To identify PRKCN as a potential therapeutic target for MM.
• To elucidate the molecular mechanisms underlying PRKCN's function in MM.

Main Methods:

• Identification of PRKCN as a super-enhancer-driven gene in MM.
• Analysis of PRKCN transactivation by NF-κB signaling.
• Assessment of PRKCN's impact on cell growth, tumorigenicity, and drug resistance via knockdown.
• Investigation of the PRKCN-IRF4 interaction and the IRF4-PRKCN feed-forward circuit.
• Exploration of PRKCN's effect on mTORC1/C2 signaling and its kinase-independent function.
• Evaluation of PRKCN inhibition using an orally bioavailable inhibitor in vitro and in vivo MM models.

Main Results:

• PRKCN is identified as a super-enhancer-driven gene associated with poor prognosis in MM.
• PRKCN is transactivated by NF-κB signaling and promotes MM cell growth and drug resistance.
• A feed-forward circuit between IRF4 and PRKCN is established, with PRKCN activating mTOR signaling to foster IRF4 expression.
• PRKCN modulates the mTOR-IRF4 axis and cell growth independently of its kinase activity but requires activation loop phosphorylation.
• PRKCN inhibition suppresses MM growth, overcomes drug resistance in vitro and in vivo, and is linked to reduced PRKCN expression and activity.
• PRKCN silencing enhances interferon signaling and sensitivity.

Conclusions:

• PRKCN links aberrant NF-κB signaling to the mTOR-IRF4 axis in multiple myeloma.
• PRKCN is a promising therapeutic target for MM, offering a strategy to overcome drug resistance.
• Targeting PRKCN with specific inhibitors demonstrates significant anti-myeloma efficacy in preclinical models.