Improving therapeutic options and reducing resistance/relapse in diffuse large B-cell lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of aggressive non-Hodgkin lymphoma (NHL). Despite the common use of the immunochemotherapy regimen R-CHOP, 40% of DLBCL patients are resistant or relapse. Better understanding the molecular pathways involved in the response to treatment is needed to improve targeted therapies as well as to identify the mechanisms of resistance in DLBCL. We investigated different compounds aiming to propose novel targeted therapies suitable to be applied in DLBCL. Also, we investigated how chemotherapy-induced senescent cells that may contribute to resistance and relapse. We found that CUDC-907 has a strong impact on DLBCL cell survival. Combination therapies showed synergism and efficacy in DLBCL cells, with the most effective being CUDC-907 and IMD-0354 (IKKβ inhibitor). We also used an IAP-based PROTAC to induce targeted degradation of HDAC1/2/3 in DLBCL cells. Traditional HDAC inhibitors lack isoform and complex selectivity to control aberrant deacetylase activity caused by disease-related elevated HDAC levels, but our PROTAC demonstrated great potential in treating DLBCL. Senescent cells can be induced by chemotherapy, which may play a role in disease resistance and relapse. Senotherapies, strategies that target senescent cells, may help reduce this effect. We investigated the relationship between senescence induction and chemo-resistance in DLBCL cells. We observed that senescence was induced by Doxorubicin in our model. This resulted in increased DLBCL cell proliferation, indicating a link between chemotherapy resistance and senescence induction in DLBCL cells. This suggests preventing senescent cell accumulation after chemotherapy may be beneficial in DLBCL. In light of this, we investigated the effect of senolytics in DLBCL senescent cells. We found that CUDC-907 is also a promising therapeutic strategy for senescent DLBCL cell elimination that could be benefit as adjuvants to standard treatment. All these discoveries suggest alternative effective therapies for DLBCL that should be next tested clinically.