Dual Inhibition of Canonical and Noncanonical NF-κB Pathways Demonstrates Significant Antitumor Activities in Multiple Myeloma

Abstract

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.

NF-κB Transcriptional Activity Is Modulated by FK506-binding Proteins FKBP51 and FKBP52

“…Because NF-B is also an essential protein in the immunological response against cancer, there has been a reluctance to use NF-B-targeting inhibitors for the treatment of such malignancies. Nevertheless, combining classical chemotherapeutics with inhibitors of NF-B activation seems to result in a promising synergistic strategy (72,73). Elevated NF-B activity and/or higher half-life persistence in the nucleus of cancer cells (like that evidenced with greater amounts of FKBP52 in Fig.…”

B-cell receptor signaling as a driver of lymphoma development and evolution

“…In part this may be due to NF-κB being a major downstream effector in the BCR pathway that conveys pro-survival and proliferation signaling [2;85]. NF-κB upregulates anti-apoptotic BCL2-family members [60], whose function is now also directly targeted with specific antagonists in clinical trials [86].…”

“…PBS-1086, a pan-Rel inhibitor that decreases DNA binding of subunits in both the canonical (p65, p50, Rel-C) and non-canonical (p52, Rel-B) NF-κB pathway was recently shown in vitro and in xenograft models of multiple myeloma to inhibit NF-κB activity. Apoptosis was induced in the models and synergism with bortezomib was demonstrated, in vitro effect was also demonstrated in CLL cells [85;87]. However, due to the ubiquitous role of NF-κB signaling, targeting this pathway directly could result in unwanted effects in other organ systems.…”

An update on molecular biology and drug resistance mechanisms of multiple myeloma

“…The apoptotic function of bortezomib is partly explained by blocking canonical NF-B pathway. However, in bortezomib resistance, it induces the alternative non-canonical pathway (Fabre et al, 2012). Bortezomib resistance may also develop through proteasome inhibitor resistant (PIR) pathway (Markovina et al, 2008).…”