Targeting Mantle Cell Lymphoma with a Strategy of Combined Proteasome and Histone Deacetylase Inhibition

Although approved for over a decade, the clinical utility of proteasome inhibitors (PIs) remains largely restricted to the treatment of patients with multiple myeloma (MM) and mantle cell lymphoma (MCL). This has fueled interest in understanding mechanisms of resistance to their antineoplastic actions, leading to the development of new and improved PIs (e.g., carfilzomib, ixazomib, marizomib) and rational combinations with other novel classes of targeted agents. With respect to the latter, histone deacetylase inhibitors (HDACIs) represent one of the most extensively studied classes of agents. PIs and HDACIs interact at multiple levels to trigger synergistic cell killing in a variety of tumor types through multiple mechanisms, including induction of oxidative stress and DNA damage, PI-mediated inhibition of the cytoprotective NF-κB pathway activated by HDACIs, and promotion of proteotoxic stress through simultaneous proteasome inhibition and disruption of aggresome formation and chaperone proteins, leading to the accumulation of M. Batalo Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA P. Bose • B. Holkova Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA S. Grant, M.D. (*) Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA e-mail: [email protected] * Author contributed equally with all other contributors.