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MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-B–dependent lymphoma
Michael A. Milhollen1,*, Tary Traore1,*, Jennifer Adams-Duffy1, Michael P. Thomas1, Allison J. Berger1, Lenny Dang1, Lawrence R. Dick1, James J. Garnsey1, Erik Koenig1, Steven P. Langston1, Mark Manfredi1, Usha Narayanan1, Mark Rolfe1, Louis M. Staudt2, Teresa A. Soucy1, Jie Yu1, Julie Zhang1, Joseph B. Bolen1, and Peter G. Smith1
MLN4924 is a potent and selective small molecule NEDD8-activating enzyme (NAE) inhibitor. In most cancer cells tested, inhibition of NAE leads to induction of DNA rereplication, resulting in DNA damage and cell death. However, in preclinical models of activated B cell–like (ABC) diffuse large B-cell lymphoma (DLBCL), we show that MLN4924 induces an alternative mechanism of action. Treatment of ABC DLBCL cells with MLN4924 resulted in rapid accumulation of pIB, decrease in nuclear p65 content, reduction of nuclear factor-B (NF-B) transcriptional activity, and G1 arrest, ultimately resulting in apoptosis induction, events consistent with potent NF-B pathway inhibition. Treatment of germinal-center B cell–like (GCB) DLBCL cells resulted in an increase in cellular Cdt-1 and accumulation of cells in S-phase, consistent with cells undergoing DNA rereplication. In vivo administration of MLN4924 to mice bearing human xenograft tumors of ABC- and GCB-DLBCL blocked NAE pathway biomarkers and resulted in complete tumor growth inhibition. In primary human tumor models of ABC-DLBCL, MLN4924 treatment resulted in NF-B pathway inhibition accompanied by tumor regressions. This work describes a novel mechanism of targeted NF-B pathway modulation in DLBCL and provides strong rationale for clinical development of MLN4924 against NF-B–dependent lymphomas.
