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

IT-901 is a novel and selective NF-kB inhibitor with promising activity in pre-clinical models. Here we show that treatment of chronic lymphocytic leukemia cells with IT-901 effectively interrupts NF-kB transcriptional activity. Chronic lymphocytic leukemia 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-kB signaling in stromal and myeloid cells, both tumor-supportive elements, fails to induce apoptosis, but impairs NF-kB-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. Its anti-tumor properties are confirmed in xenograft models of chronic lymphocytic leukemia and in Richter syndrome patient-derived xenografts, with documented NF-kB inhibition and significant reduction of tumor burden. Together, these results provide preclinical proof of principle for IT-901 as a potential new drug in chronic lymphocytic leukemia and Richter syndrome.