Abstract 5538: Development of HDACi resistance in DLBCL leads to a switch in subtype towards a more differentiated B-cell and is associated with increased sensitivity to proteasome inhibition

Abstract

Abstract Diffuse Large B Cell Lymhoma (DLBCL) is a highly heterogeneous disease in terms of clinical presentation, cell morphology, molecular characteristics and response to therapy. Gene expression profiling studies in patients have indicated that DLBCL can be sub-classified in relationship to the different stages of normal B cell development at which the cancer arises; germinal center B cell (GCB) and activated B cell (ABC). More recently, a similar approach distinguished three different reproducible clusters referred to as oxidative phosphorylation (OxPhos), B cell receptor/proliferation (BCR) and host response (HR). Importantly, DLBCL has also been well characterized at the genomic level. A large number of genes encoding epigenetic modifying enzymes are mutated in DLBCL, which implicates epigenetic regulation as an important factor in DLBCL pathogenesis, and a potential target for therapy. Among epigenetic therapies, histone deacetylase inhibitors (HDACi) have shown some clinical activity in DLBCL patients ranging from 5 to 25%, although responsive patients ultimately develop resistance. Aiming to understand resistance and response to HDACi in DLBCL, we developed HDACi-resistant cell lines from the GCB and BCR subtype cells SUDHL6 and SUDHL4. Gene expression array analysis was performed in parental SUDHL6 and the resistant clone SUDHL6-X. Strikingly, we found that the resistant cells have switched gene expression profile from GCB to ABC subtype and from BCR to OXPHOS. Also, we observe features of more differentiated, plasmablast-like cells in SUDHL6-X cells and in all other resistant subclones we developed, including inactivated B cell receptor signaling, increased endoplasmic reticulum stress and activation of the unfolded protein response. These characteristics are reflected in a distinctive response pattern to other targeted drugs. We observe that HDACi-resistant cells become cross-resistant to the anti-CD20 antibody rituximab, but, interestingly, they gain susceptibility to inhibitors of the proteasome bortezomib and MLN2238. Importantly, analysis of lymphoma cells isolated from de novo resistant DLBCL patients treated with the HDACi panobinostat for 15 days showed a switch in gene expression profiles from GCB to ABC, similar to SUDHL6X cells, indicating that our observations are not exclusive of in vitro systems. In conclusion, we have shown for the first time that resistance to HDACi is associated with differentiation of lymphoma cells that we predict makes them insensitive to drugs targeting the B cell receptor and anti-CD20 antibody, but sensitive to proteasome inhibition. Citation Format: Daphné Dupéré-Richer, Mena Kinal, Filippa Pettersson, Mona Hassawi, Yang ShaoNing, Torsten H. Nielsen, Kathleen Klein, Teresa Ezponda-Itoiz, Jonathan D. Licht, Nathalie Johnson, Sarit E. Assouline, Leandro Cerchietti, Wilson H. Miller, Koren K. Mann. Development of HDACi resistance in DLBCL leads to a switch in subtype towards a more differentiated B-cell and is associated with increased sensitivity to proteasome inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5538. doi:10.1158/1538-7445.AM2014-5538