Dual inhibition of histone deacetylases and phosphoinositide 3-kinase enhances therapeutic activity against B cell lymphoma

Abstract

// Patrizia Mondello 1 , Enrico Derenzini 1 , Zahra Asgari 1 , John Philip 2 , Elliott J. Brea 3 , Venkatraman Seshan 4 , Ronald C. Hendrickson 2 , Elisa de Stanchina 5 , David A. Scheinberg 3 , Anas Younes 1 1 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 2 Proteomics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA 3 Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA 4 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5 Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA Correspondence to: Anas Younes, email: younesa@mskcc.org Keywords: MYC, PI3K, DLBCL, BCR pathway Received: September 28, 2016      Accepted: January 02, 2017      Published: January 28, 2017 ABSTRACT Phosphoinositide 3-kinase (PI3K) and Myc are known to cooperate in promoting the survival and growth of a variety of B-cell lymphomas. While currently there are no small molecule inhibitors of Myc protein, histone deacetylase (HDAC) inhibitors have been shown to reduce levels of Myc protein by suppressing its transcription. We assessed the efficacy of CUDC-907, a new rationally designed dual inhibitor of PI3K and HDACs, in a panel of lymphoma cell lines. CUDC-907 treatment resulted in a dose- and time-dependent growth inhibition and cell death of DLBCL cell lines, irrespective of the cell of origin. CUDC-907 treatment down-regulated the phosphorylation of PI3K downstream targets, including AKT, PRAS40, S6, and 4EBP1, increased histone 3 acetylation, and decreased Myc protein levels. SILAC-based quantitative mass spectrometry demonstrated that CUDC-907 treatment decreased the protein levels of several components of the B cell receptor (BCR) and Toll like receptor (TLR) pathways, including BTK, SYK, and MyD88 proteins. These cellular changes were associated with an inhibition of NF-kB activation. CUDC-907 demonstrated in vivo efficacy with no significant toxicity in a human DLBCL xenograft mouse model. Collectively, these data provide a mechanistic rationale for evaluating CUDC-907 for the treatment of patients with Myc and PI3K-dependent lymphomas.