Dual inhibition of canonical and non-canonical NF-κB pathways demonstrates significant anti-tumor activities in multiple myeloma
Menée sur des lignées celulaires et à l'aide de xénogreffes, cette étude évalue un composé appelé PBS-1086, un inhibiteur des voies canonique et non canonique de signalisation NF-kappaB, pour le traitement d'un myélome multiple en combinaison avec le bortezomib
Purpose: NF-
κB transcription factor plays a key role in the pathogenesis of multiple myeloma (MM) in the context of the bone marrow (BM) microenvironment. Both canonical and non-canonical pathways contribute to total NF-κB activity. Recent studies have demonstrated a critical role for the non-canonical pathway: selective inhibitors of the canonical pathway present a limited activity, mutations of the non-canonical pathway are frequent, and bortezomib-induced cytotoxicity cannot be fully attributed to inhibition of canonical NF-κB activity. Experimental design: MM cell lines, primary patient cells, and the human MM xenograft murine model were used to examine the biologic impact of dual inhibition of both canonical and non-canonical NF-κB pathways. Results: We show that PBS-1086 induces potent cytotoxicity in MM cells, but not in peripheral blood mononuclear cells. PBS-1086 overcomes the proliferative and anti-apoptotic effects of the BM milieu, associated with inhibition of NF-κB activity. Moreover, PBS-1086 strongly enhances the cytotoxicity of bortezomib in bortezomib-resistant MM cell lines and patient MM cells. PBS-1086 also inhibits osteoclastogenesis through an inhibition of RANKL-induced NF-κB activation. Finally, in a xenograft model of human MM in the BM milieu, PBS-1086 shows significant in vivo anti-MM activity and prolongs host survival, associated with apoptosis and inhibition of both NF-κB pathways in tumor cells. Conclusions: Our data demonstrate that PBS-1086 is a promising dual inhibitor of the canonical and non-canonical NF-κB pathways. Our preclinical study therefore provides the framework for clinical evaluation of PBS-1086 in combination with bortezomib for the treatment of MM and related bone lesions.