Panobinostat acts synergistically with ibrutinib in diffuse large B cell lymphoma cells with MyD88 L265P mutations
Patrizia Mondello, Elliott J. Brea, Elisa De Stanchina, Eneda Toska, Aaron Y. Chang, Myles Fennell, Venkatraman Seshan, Ralph Garippa, David A. Scheinberg, José Baselga, Hans-Guido Wendel, and Anas Younes
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First published November 15, 2018 - More info
JCI Insight. 2018;3(22):e125568. https://doi.org/10.1172/jci.insight.125568.
Copyright © 2018, American Society for Clinical Investigation
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Abstract
Diffuse large B cell lymphoma (DLBCL) frequently harbors genetic alterations that activate the B cell receptor (BCR) and TLR pathways, which converge to activate NF-κB. While selective inhibition of BTK with ibrutinib causes clinical responses in relapsed DLBCL patients, most responses are partial and of a short duration. Here, we demonstrated that MyD88 silencing enhanced ibrutinib efficacy in DLBCL cells harboring MyD88 L265P mutations. Chemical downregulation of MyD88 expression with HDAC inhibitors also synergized with ibrutinib. We demonstrate that HDAC inhibitor regulation of MyD88 expression is mediated by STAT3. In turn, STAT3 silencing caused a decrease in MyD88 mRNA and protein levels, and enhanced the ibrutinib antilymphoma effect in MyD88 mutant DLBCL cells. Induced mutations in the STAT3 binding site in the MyD88 promotor region was associated with a decrease in MyD88 transcriptional activity. We also demonstrate that treatment with the HDAC inhibitor panobinostat decreased phosphorylated STAT3 binding to the MyD88 promotor. Accordingly, combined treatment with panobinostat and ibrutinib resulted in enhanced inhibition of NF-κB activity and caused regression of DLBCL xenografts. Our data provide a mechanistic rationale for combining HDAC inhibitors and ibrutinib for the treatment of DLBCL.
Authors
Patrizia Mondello, Elliott J. Brea, Elisa De Stanchina, Eneda Toska, Aaron Y. Chang, Myles Fennell, Venkatraman Seshan, Ralph Garippa, David A. Scheinberg, José Baselga, Hans-Guido Wendel, Anas Younes
Original citation: JCI Insight. 2017;2(6):1–14. https://doi.org/10.1172/jci.insight.90196
Citation for this corrigendum: JCI Insight. 2018;3(22):e125568. https://doi.org/10.1172/jci.insight.125568
David A. Scheinberg’s conflict-of-interest statement was not included in the manuscript. The correct statement is below.
DAS sits on boards for, was a consultant to, and/or owns stock or options in Sellas Life Sciences, Progenics Pharmaceuticals, Actinium Pharmaceuticals Inc., and Great Point Partners, companies that are not germane to the work in this paper. DAS owned stock in the following companies: Johnson & Johnson, Pfizer, and Abbott as well as DaVita, Intuitive Surgical, Edwards Lifesciences, Sapience Therapeutics, and ContraFect Corp.; these latter companies are not related to the work in this paper. DAS is an inventor on patents (US patent nos. 10,040,865, 9,976,137, 9,919,037, 9,289,519, 8,486,409, 6,156,316, 5,730,982, 6,603,127, 7,488,718, and 7,747,395) owned by Memorial Sloan Kettering Cancer Center and not germane to the work in this paper.
The authors regret the error.
