title: Panobinostat acts synergistically with ibrutinib in diffuse large B cell lymphoma cells with MyD88 L265P mutations.
abstract: Diffuse large B cell lymphoma (DLBCL) frequently harbors genetic alterations that activate the B cell receptor (BCR) and TLR pathways, which converge to activate NF-κB. While selective inhibition of BTK with ibrutinib causes clinical responses in relapsed DLBCL patients, most responses are partial and of a short duration. Here, we demonstrated that MyD88 silencing enhanced ibrutinib efficacy in DLBCL cells harboring MyD88 L265P mutations. Chemical downregulation of MyD88 expression with HDAC inhibitors also synergized with ibrutinib. We demonstrate that HDAC inhibitor regulation of MyD88 expression is mediated by STAT3. In turn, STAT3 silencing caused a decrease in MyD88 mRNA and protein levels, and enhanced the ibrutinib antilymphoma effect in MyD88 mutant DLBCL cells. Induced mutations in the STAT3 binding site in the MyD88 promotor region was associated with a decrease in MyD88 transcriptional activity. We also demonstrate that treatment with the HDAC inhibitor panobinostat decreased phosphorylated STAT3 binding to the MyD88 promotor. Accordingly, combined treatment with panobinostat and ibrutinib resulted in enhanced inhibition of NF-κB activity and caused regression of DLBCL xenografts. Our data provide a mechanistic rationale for combining HDAC inhibitors and ibrutinib for the treatment of DLBCL.
authors.affiliation: Department of Medicine.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mondello
authors.affiliation: Molecular Pharmacology Program.
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Brea
authors.affiliation: Antitumor Assessment Core.
authors.forename: Elisa
authors.initials: E
authors.lastname: De Stanchina
authors.affiliation: Human Oncology and Pathogenesis.
authors.forename: Eneda
authors.initials: E
authors.lastname: Toska
authors.affiliation: Molecular Pharmacology Program.
authors.forename: Aaron Y
authors.initials: AY
authors.lastname: Chang
authors.affiliation: RNAi and Gene Editing Core Facility.
authors.forename: Myles
authors.initials: M
authors.lastname: Fennell
authors.affiliation: Department of Epidemiology and Biostatistics.
authors.forename: Venkatraman
authors.initials: V
authors.lastname: Seshan
authors.affiliation: RNAi and Gene Editing Core Facility.
authors.forename: Ralph
authors.initials: R
authors.lastname: Garippa
authors.affiliation: Molecular Pharmacology Program.
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
authors.affiliation: Human Oncology and Pathogenesis.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Hans-Guido
authors.initials: HG
authors.lastname: Wendel
authors.affiliation: Department of Medicine.
authors.forename: Anas
authors.initials: A
authors.lastname: Younes
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D000077767:Panobinostat / Q000494:pharmacology*; D010880:Piperidines; D011401:Promoter Regions, Genetic; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C551803:ibrutinib; D000077767:Panobinostat; D000225:Adenine