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 IC50 values 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 vivo confirmation 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.
Subject(s)
Histone Deacetylase 6/antagonists & inhibitors , Histone Deacetylase Inhibitors/administration & dosage , Hydroxamic Acids/administration & dosage , Lymphoma/drug therapy , Pyrimidines/administration & dosage , Adenine/analogs & derivatives , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Apoptosis/drug effects , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Drug Synergism , Histone Deacetylase 6/genetics , Humans , Lymphoma/genetics , Lymphoma/pathology , Mice , Piperidines , Pyrazoles/administration & dosage , Xenograft Model Antitumor AssaysABSTRACT
How can self-knowledge of personality be improved? What path is the most fruitful source for learning about our true selves? Previous research has noted two main avenues for learning about the self: looking inward (e.g., introspection) and looking outward (e.g., feedback). Although most of the literature on these topics does not directly measure the accuracy of self-perceptions (i.e., self-knowledge), we review these paths and their potential for improving self-knowledge. We come to the conclusion that explicit feedback, a largely unexamined path, is likely a fruitful avenue for learning about one's own personality. Specifically, we suggest that self-knowledge might be fully realized through the use of explicit feedback from close, knowledgeable others. As such, we conclude that the road to self-knowledge likely cannot be traveled alone but must be traveled with close others who can help shed light on our blind spots.
