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

Multiple myeloma (MM) remains incurable, necessitating development of novel therapeutic targets. Deregulated PRKCN is implicated in solid tumors, while its role in MM remains elusive. Here, PRKCN is identified as a super-enhancer-driven gene associated with adverse prognosis in MM. PRKCN is transactivated by NF-κB signaling intrinsically existing or exogenously provoked. Constitutive or inducible knockdown of PRKCN significantly impairs cell growth and tumorigenicity, while overcoming drug resistance. PRKCN harnesses IRF4 to exert its effect, and in turn, IRF4 directly induces PRKCN transcription, establishing a feed-forward IRF4-PRKCN circuit. Furthermore, PRKCN fosters IRF4 expression by activating mTORC1/C2 signaling pathways via physical interaction with mTOR. Surprisingly, PRKCN modulates mTOR-IRF4 axis and cell growth independently of its acknowledged kinase activity yet requiring activation loop phosphorylation. Intriguingly, PRKCN silencing evokes interferon signaling and confers increased sensitivity to interferon. Finally, targeting PRKCN with an orally bioavailable inhibitor suppresses MM cell growth and overcomes drug resistance in vitro, and elicits robust efficacy in cell line-derived xenografts and a patient-derived xenograft, which is connected with the mitigated PRKCN expression and activation loop phosphorylation as well as blunted mTOR-IRF4 axis. Collectively, our study delineates PRKCN function that links aberrant NF-κB signaling and mTOR-IRF4 axis, supporting clinically targeting PRKCN in MM.