title: HDAC inhibitor AR-42 decreases CD44 expression and sensitizes myeloma cells to lenalidomide.
abstract: Multiple myeloma (MM) is a hematological malignancy of plasma cells in the bone marrow. Despite multiple treatment options, MM is inevitably associated with drug resistance and poor outcomes. Histone deacetylase inhibitors (HDACi's) are promising novel chemotherapeutics undergoing evaluation in clinical trials for the potential treatment of patients with MM. Although in preclinical studies HDACi's have proven anti-myeloma activity, but in the clinic single-agent HDACi treatments have been limited due to low tolerability. Improved clinical outcomes were reported only when HDACi's were combined with other drugs. Here, we show that a novel pan-HDACi AR-42 downregulates CD44, a glycoprotein that has been associated with lenalidomide and dexamethasone resistance in myeloma both in vitro and in vivo. We also show that this CD44 downregulation is in part mediated by miR-9-5p, targeting insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), which directly binds to CD44 mRNA and increases its stability. Importantly, we also demonstrate that AR-42 enhances anti-myeloma activity of lenalidomide in primary MM cells isolated from lenalidomide resistant patients and in in vivo MM mouse model. Thus, our findings shed light on potential novel combinatorial therapeutic approaches modulating CD44 expression, which may help overcome lenalidomide resistance in myeloma patients.
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Canella
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Hector
authors.initials: H
authors.lastname: Cordero Nieves
authors.affiliation: Department of Internal Medicine, Oncology/Hematology Fellowship, The Ohio State University, Columbus, OH, USA.
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Sborov
authors.affiliation: Lymphoma & Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Luciano
authors.initials: L
authors.lastname: Cascione
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Hanna S
authors.initials: HS
authors.lastname: Radomska
authors.affiliation: Department of Internal Medicine, Biomedical Sciences Graduate Program, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Smith
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stiff
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.|Present Address: Sanford Burnham Prebys Medical Discovery Insitute, La Jolla, CA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Consiglio
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Enrico
authors.initials: E
authors.lastname: Caserta
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Rizzotto
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zanesi
authors.affiliation: Department of Internal Medicine, Biosystems Analysis, LTTA, Department of Morphology, Surgery and Experimental Medicine, Università degli Studi, Ferrara, Italy.
authors.forename: Volinia
authors.initials: V
authors.lastname: Stefano
authors.affiliation: Department of Neurological Surgery, Dardinger Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Medical Center, Columbus, Ohio, USA.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.affiliation: Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.|Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.affiliation: Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA.
authors.forename: Yvonne A
authors.initials: YA
authors.lastname: Efebera
authors.affiliation: Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA.
authors.forename: Craig C
authors.initials: CC
authors.lastname: Hofmeister
authors.affiliation: Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.|Department of Internal Medicine, Division of Hematology, The Ohio State University, Columbus, OH, USA.
authors.forename: Flavia
authors.initials: F
authors.lastname: Pichiorri
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D000077269:Lenalidomide; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010654:Phenylbutyrates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; C497483:CD44 protein, human; D056572:Histone Deacetylase Inhibitors; D018960:Hyaluronan Receptors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; D012333:RNA, Messenger; D013792:Thalidomide; D000077269:Lenalidomide
keywords: CD44; IGF2BP3; lenalidomide; miR-9–5p; myeloma