Abstract
Despite advances in deciphering the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL), patients with relapsed/refractory disease, particularly those with adverse genetic features (e.g., mutated p53 or double hit lymphoma (DHL)) have very poor prognoses, and effective therapies are lacking. In this study we examined the preclinical efficacy and associated biological effects of the first oral proteasome inhibitor, ixazomib, in DLBCL in vitro and in vivo models. We demonstrated that ixazomib exhibited anti-tumor activities in 28 representative DLBCL cell lines, 10 primary DLBCL samples, and a DHL xenotransplant mouse model, at clinically achievable drug concentrations. Ixazomib sensitivity in DLBCL cells is correlated with immunoproteasomal activity; stimulating lymphoma cells with interferon gamma induced immunoproteasome activity and sensitized these cells to ixazomib. In addition, we showed that ixazomib induces apoptosis and the DNA damage response pathway, through activation of the checkpoint kinase 2 (CHK2). Hence, pharmacological inhibition of CHK2 enhances the anti-tumor activity of ixazomib in DLBCL cells. Our results indicate that ixazomib is an effective proteasome inhibitor active in DLBCL, including DHL, and its combination with a CHK2 inhibitor offers a potentially more robust therapeutic regimen for treatment-resistant DLBCL.
Highlights
Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, is characterized by clinical, genetic, and biological heterogeneity [1]
Since ixazomib effectively inhibits diffuse large B-cell lymphoma (DLBCL) cell viability, we examined whether the drug can induce apoptosis and/ or cell cycle arrest in two representative DLBCL cell lines (RC and MZ), shown to be highly sensitive to ixazomib
Earlier studies have shown that the novel proteasome inhibitor ixazomib has in vitro and vitro antitumor activity in DLBCL, its efficacy in high-risk DLBCL, including double-hit lymphoma (DHL), has yet to be examined [14, 23]
Summary
Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, is characterized by clinical, genetic, and biological heterogeneity [1]. The current frontline chemotherapy regimen for DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Using this regimen, about 60% of patients are cured with the remaining patients experiencing either refractory (~10%) or relapse (~30%) disease within 2–3 years. 2–3% of DLBCL cases with rearrangements of MYC and either the BCL2 or BCL6 gene, so-called double-hit lymphoma (DHL), are associated with the germinal center B-cell (GCB) phenotype, frequent extranodal and central nervous system involvement, higher International Prognostic Index scores, poor response to R-CHOP therapy, and overall dismal outcome [2,3,4,5,6]. Investigation of novel therapeutic approaches for relapsed/refractory DLBCL as well as DHL is underway, but lack of relevant human experimental models for understanding the biological basis of these cancers has hampered the identification of valid therapeutic regimens
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