Epigenetic inhibitors sensitize DLBCL cells to rituximab and doxorubicin

Primary therapy for diffuse large B-cell lymphoma (DLBCL) is an immunochemotherapy regimen comprising rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). While R-CHOP cures 60% of the patients with DLBCL, those who do not respond or relapse have dismal prognosis, and effective treatment strategies are needed. Due to the plastic nature of the epigenome and its fundamental role in regulating cell identity, we hypothesized that reprogramming the epigenome can overcome resistance to R-CHOP. We developed a novel drug screening protocol to identify epigenetic modifiers that sensitize DLBCL cell lines to immunochemotherapy. Of the herein tested 60 epigenetic compounds, we identified several histone deacetylase (HDAC) and histone methyltransferase (HMT) inhibitors that acted synergistically with immunochemotherapy. We show that sensitization through HDAC and HMT inhibitors is achieved by dysregulating homologous recombination, a central DNA repair pathway, as well as by disrupting the cell cycle and affecting the apoptotic pathway. Epigenetic inhibitors are well-tolerated, which together with our findings support their use in combination with immunochemotherapy in patients with primary refractory and relapsed DLBCL.