15 research outputs found
PI3K/Akt/mTOR Pathway Inhibition in Chemotherapy-Sensitive and -Resistant Models of Burkitt Lymphoma
Pevonedistat, a NEDD8âactivating enzyme inhibitor, induces apoptosis and augments efficacy of chemotherapy and small molecule inhibitors in preâclinical models of diffuse large Bâcell lymphoma
Abstract We studied the biological activity of pevonedistat, a firstâinâclass NEDD8âactivating enzyme (NAE) inhibitor, in combination with various cytotoxic chemotherapy agents and small molecule inhibitors in lymphoma preclinical models. Pevonedistat induced cell death in activated Bâcell (ABC) diffuse large Bâcell lymphoma (DLBCL) cell lines and to a lesser degree in germinal center Bâcell (GCB) DLBCL cell lines. In pevonedistat sensitive cells, we observed inhibition of NFâÎşB activity by p65 coâlocalization studies, decreased expression of BCLâ2/BclâXL, and upregulation of BAK levels. Pevonedistat enhanced the activity of cytarabine, cisplatin, doxorubicin, and etoposide in ABCâ, but not in the GCBâDLBCL cell lines. It also exhibited synergy with ibrutinib, selinexor, venetoclax, and Aâ1331852 (a novel BCLâXL inhibitor). In vivo, the combination of pevonedistat and ibrutinib or pevonedistat and cytarabine prolonged survival in SCID mice xenograft models when compared with monotherapy controls. Our data suggest that targeting the neddylation pathway in DLBCL is a viable therapeutic strategy and support further clinical studies of pevonedistat as a single agent or in combination with chemotherapy or novel targeted agents