Dual inhibition of histone deacetylases and phosphoinositide 3-kinase enhances therapeutic activity against B cell lymphoma.
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.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Patrizia
P
Mondello
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Enrico
E
Derenzini
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Zahra
Z
Asgari
Proteomics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
John
J
Philip
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Elliott J
EJ
Brea
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Venkatraman
V
Seshan
Proteomics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Ronald C
RC
Hendrickson
Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Elisa
E
de Stanchina
Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
David A
DA
Scheinberg
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Anas
A
Younes
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000473:pathology*; D013058:Mass Spectrometry; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C576940:CUDC-907; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D006655:Histone Deacetylases
BCR pathway; DLBCL; MYC; PI3K