Targeting metabolism and survival in chronic lymphocytic leukemia and Richter syndrome cells by a novel NF-?B inhibitor.

ABSTRACT: IT-901 is a novel and selective NF-?B inhibitor with promising activity in pre-clinical models. Here we show that treatment of chronic lymphocytic leukemia cells (CLL) with IT-901 effectively interrupts NF-?B transcriptional activity. CLL cells exposed to the drug display elevated mitochondrial reactive oxygen species, which damage mitochondria, limit oxidative phosphorylation and ATP production, and activate intrinsic apoptosis. Inhibition of NF-?B signaling in stromal and myeloid cells, both tumor-supportive elements, fails to induce apoptosis, but impairs NF-?B-driven expression of molecules involved in cell-cell contacts and immune responses, essential elements in creating a pro-leukemic niche. The consequence is that accessory cells do not protect CLL cells from IT-901-induced apoptosis. In this context, IT-901 shows synergistic activity with ibrutinib, arguing in favor of combination strategies. IT-901 is also effective in primary cells from patients with Richter syndrome (RS). Its anti-tumor properties are confirmed in xenograft models of CLL and in RS patient-derived xenografts, with documented NF-?B inhibition and significant reduction of tumor burden. Together, these results provide pre-clinical proof of principle for IT-901 as a potential new drug in CLL and RS.

SUBMITTER: Vaisitti T 

PROVIDER: S-EPMC5664392 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature