Selective Inhibition of Histone Deacetylase 6 (HDAC6) and HDAC3 As a Novel Therapeutic Strategy in Mantle Cell Lymphoma (MCL)

In recent years, the deeper understanding of the molecular alterations that occurs in MCL has provided the foundation for the development of new targeted therapeutic approaches. Histone deacetylases (HDACs), represent ideal targets due to their dual role not only in supporting lymphoma survival and resistance to apoptosis^1,2, but also in immunologic escape and autocrine cytokine signaling which maintains the microenvironmental niche and facilitates drug resistance^3,4.

Recently, we have identified two members of the HDAC family, HDAC6 and HDAC3, which play integral roles in regulation of 1) survival/apoptosis, 2) microenvironment-mediated drug resistance, and 3) immunogenicity of MCL cells. Our studies to date have shown the following: First, HDAC6 and HDAC3 are overexpressed in MCL cell lines and primary cells from MCL patients. This expression is further up-regulated following adhesion of MCL cells to stromal cells, consequently increasing survival and acquisition of a drug-resistance phenotype. Second, genetic or pharmacologic inhibition of HDAC6 with isotype-selective inhibitor(s) induced cell cycle arrest, apoptosis and overcome stroma-mediated drug resistance. Of note, MCL cells lacking HDAC6 are more immunogenic and able of inducing stronger antitumor responses. This increased immunogenicity is due to a novel mechanism involving HDAC6 regulation of the immunosuppressive STAT3 signaling pathway and PD-L1 expression. Strikingly, mice lacking HDAC6 (germ-line HDAC6KO) displayed significantly reduced tumor growth kinetics when compared to the wild-type controls. Third, Genetic or pharmacologic disruption of HDAC3 resulted in decreased cell proliferation, increased apoptosis and reversal of the drug-resistance phenotype of MCL cells. This is due to HDAC3-mediated regulation of a group of small non-coding tumor suppressor microRNAs (miR-15a/16-1, miR-26 and miR29). The importance of HDAC3 as a promising therapeutic target in MCL is further highlighted by our recent findings using the HDAC3-selective inhibitor RGFP966 in human MCL cells, Four,strategies targeting both, HDAC6 and HDAC3 with selective inhibitors represent a promising strategy in MCL specially when these novel agents are combined with the BTK inhibitor Ibrutinib. Although inhibition of HDACs are extensively known for their ability to induce cell cycle arrest and apoptosis of malignant cells, their immuneregulatory effects upon tumor cell and/or immune cells are yet to be elucidated. In this study we present data that can convincingly provide a proper framework for combinatorial therapy using HDAC inhibitors in MCL.

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2. Kawamata N, et alBlood 2007; 110(7): 2667-73.

3. Lwin T, et alLeukemia 2007; 21(7): 1521-31.

4. Meads MB, et alNat Rev Cancer 2009; 9(9): 665-74.