title: Mechanisms of Acquired Drug Resistance to the HDAC6 Selective Inhibitor Ricolinostat Reveals Rational Drug-Drug Combination with Ibrutinib.
abstract: Purpose:Pan-class I/II histone deacetylase (HDAC) inhibitors are effective treatments for select lymphomas. Isoform-selective HDAC inhibitors are emerging as potentially more targeted agents. ACY-1215 (ricolinostat) is a first-in-class selective HDAC6 inhibitor. To better understand the discrete function of HDAC6 and its role in lymphoma, we developed a lymphoma cell line resistant to ACY-1215.Experimental Design:The diffuse large B-cell lymphoma cell line OCI-Ly10 was exposed to increasing concentrations of ACY-1215 over an extended period of time, leading to the development of a resistant cell line. Gene expression profiling (GEP) was performed to investigate differentially expressed genes. Combination studies of ACY-1215 and ibrutinib were performed in cell lines, primary human lymphoma tissue, and a xenograft mouse model.Results:Systematic incremental increases in drug exposure led to the development of distinct resistant cell lines with IC50values 10- to 20-fold greater than that for parental lines. GEP revealed upregulation of MAPK10, HELIOS, HDAC9, and FYN, as well as downregulation of SH3BP5 and LCK. Gene-set enrichment analysis (GSEA) revealed modulation of the BTK pathway. Ibrutinib was found to be synergistic with ACY-1215 in cell lines as well as in 3 primary patient samples of lymphoma.In vivoconfirmation of antitumor synergy was demonstrated with a xenograft of DLBCL.Conclusions:The development of this ACY-1215-resistant cell line has provided valuable insights into the mechanistic role of HDAC6 in lymphoma and offered a novel method to identify rational synergistic drug combinations. Translation of these findings to the clinic is underway.Clin Cancer Res; 23(12); 3084-96. ©2016 AACR.
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York. jea2149@columbia.edu.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Amengual
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors.forename: Sathyen A
authors.initials: SA
authors.lastname: Prabhu
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Lombardo
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors.forename: Kelly
authors.initials: K
authors.lastname: Zullo
authors.affiliation: Stanford University School of Medicine, Stanford, California.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Johannet
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors.forename: Yulissa
authors.initials: Y
authors.lastname: Gonzalez
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors.forename: Luigi
authors.initials: L
authors.lastname: Scotto
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors.forename: Xavier Jirau
authors.initials: XJ
authors.lastname: Serrano
authors.affiliation: Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, New York.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Duong
authors.affiliation: Division of Clinical Pathology, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Renu
authors.initials: R
authors.lastname: Nandakumar
authors.affiliation: Division of Clinical Pathology, Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.
authors.forename: Serge
authors.initials: S
authors.lastname: Cremers
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Verma
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Center for Lymphoid Malignancies, Columbia University Medical Center, New York, New York.
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D000073864:Histone Deacetylase 6 / Q000037:antagonists & inhibitors* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D010880:Piperidines; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D000225:Adenine; C572255:ricolinostat