BTK inhibitor ibrutinib is cytotoxic to myeloma and potently enhances bortezomib and lenalidomide activities through NF-κB.

摘要: Ibrutinib (previously known as PCI-32765) has recently shown encouraging clinical activity in chronic lymphocytic leukaemia (CLL) effecting cell death through inhibition of Bruton's tyrosine kinase (BTK). In this study we report for the first time that ibrutinib is cytotoxic to malignant plasma cells from patients with multiple myeloma (MM) and furthermore treatment significantly augments bortezomib lenalidomide chemotherapies. We describe cytotoxicity MM mediated via an inhibitory effect on nuclear factor-κB (NF-κB) pathway. Specifically, blocks phosphorylation serine-536 p65 subunit NF-κB, preventing its translocation, resulting down-regulation anti-apoptotic proteins Bcl-xL, FLIP(L) survivin culminating caspase-mediated apoptosis within cells. Taken together these data provide a platform trials rationale use combination therapy, particularly bortezomib.