Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib

• Published in: Blood 2015-09, Vol.126 (13), p.1565-1574
• Main Authors: Sun, Baohua, Shah, Bhavin, Fiskus, Warren, Qi, Jun, Rajapakshe, Kimal, Coarfa, Cristian, Li, Li, Devaraj, Santhana G.T., Sharma, Sunil, Zhang, Liang, Wang, Michael L., Saenz, Dyana T., Krieger, Stephanie, Bradner, James E., Bhalla, Kapil N.
• Format: Article
• Language: English
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Azepines - pharmacology; Azepines - therapeutic use; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - metabolism; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - metabolism; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Humans; Lymphoid Neoplasia; Lymphoma, Mantle-Cell - drug therapy; Lymphoma, Mantle-Cell - metabolism; Lymphoma, Mantle-Cell - pathology; Mice, Inbred NOD; Mice, SCID; NF-kappa B - metabolism; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - metabolism; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-myc - metabolism; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Transcription Factor RelA - metabolism; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Triazoles - pharmacology; Triazoles - therapeutic use
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-04-639542

Mantle cell lymphoma (MCL) cells exhibit increased B-cell receptor and nuclear factor (NF)-κB activities. The bromodomain and extra-terminal (BET) protein bromodomain 4 is essential for the transcriptional activity of NF-κB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and cyclin-dependent kinase (CDK)4/6, inhibits the nuclear RelA levels and the expression of NF-κB target genes, including Bruton tyrosine kinase (BTK) in MCL cells. Although lowering the levels of the antiapoptotic B-cell lymphoma (BCL)2 family proteins, BA treatment induces the proapoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Cotreatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared with each agent alone, cotreatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells, which overexpress CDK6, BCL2, Bcl-xL, XIAP, and AKT, but lack ibrutinib resistance-conferring BTK mutation. Cotreatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL. •BA reduces MYC, CDK4/6, nuclear RelA, and BTK expression and is synergistically lethal with ibrutinib in MCL cells.•Cotreatment with BA and inhibitor of BCL2, CDK4/6, or histone deacetylases is synergistically lethal against ibrutinib-resistant MCL cells.