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 IC50 values 10-20 fold greater than that for parental lines. GEP revealed up-regulation of MAPK10, HELIOS, HDAC9 and FYN, as well as down-regulation 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 anti-tumor synergy was demonstrated with a xenograft of DLBCL. Conclusion 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.

A Novel Dual HDAC6 and Tubulin Inhibitor, MPT0B451, Displays Anti-tumor Ability in Human Cancer Cells in Vitro and in Vivo

“…The development of a multi-target drug may overcome these side effects. HDAC inhibitors have been verified for cancer cell growth inhibition, cell apoptosis inducement, cell invasion, and metastasis suppression ( Amengual et al, 2015 , 2016 ). Currently, four HDAC inhibitors are approved by the FDA for T-cell lymphoma and multiple myeloma ( Kawaguchi et al, 2003 ; Aldana-Masangkay and Sakamoto, 2011 ; Liu et al, 2016 ).…”

Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials

“…Additionally, a preclinical study identified the synergistic interaction of ricolinostat and ibrutinib the first-in-class BTK (Bruton's tyrosin kinase) inhibitor in a large panel of lymphoma cell lines and in a xenograft model of lymphoma. This combination led to a marked tumor growth delay and prolonged overall survival (Amengual et al, 2017).…”

Activation of MET signaling by HDAC6 offers a rationale for a novel ricolinostat and crizotinib combinatorial therapeutic strategy in diffuse large B‐cell lymphoma

“…Ricolinostat is the first oral selective HDAC6 inhibitor with reduced class I HDAC activity to be studied clinically, and it might partner well with other compounds to enhance their efficacies in treating diverse cancers. Although the results from experimental or preclinical studies have shown that combinations of ricolinostat with lenalidomide, ibrutinib, carfilzomib or bortezomib can exert synergistic effects in multiple myeloma, DLBCL, and mantle cell lymphoma , the combination of ricolinostat with a MET inhibitor (METi) has not been investigated in DLBCL.…”