XPO1 inhibitor combination therapy with bortezomib or carfilzomib induces nuclear localization of IkBa and overcomes acquired proteasome inhibitor resistance in human multiple myeloma

Acquired proteasome-inhibitor (PI) resistance is a major obstacle in the treatment of multiple myeloma (MM). We investigated whether the clinical XPO1-inhibitor selinexor, when combined with bortezomib or carfilzomib, could overcome acquired resistance in MM. PI-resistant myeloma cell lines both in vitro and in vivo and refractory myeloma patient biopsies were treated with selinexor/ bortezomib or carfilzomib and assayed for apoptosis. Mechanistic studies included NFkB pathway protein expression assays, immunofluorescence microscopy, ImageStream flowcytometry, and proximity-ligation assays. IkBa knockdown and NFkB activity were measured in selinexor/ bortezomib-treated MM cells. We found that selinexor restored sensitivity of PI-resistant MM to bortezomib and carfilzomib. Selinexor/ bortezomib treatment inhibited PI-resistant MM tumor growth and increased survival in mice. Myeloma cells from PI-refractory MM patients were sensitized by selinexor to bortezomib and carfilzomib without affecting non-myeloma cells. Immunofluorescence microscopy, Western blot, and ImageStream analyses of MM cells showed increases in total and nuclear IkBa by selinexor/ bortezomib. Proximity ligation found increased IkBa-NFkB complexes in treated MM cells. IkBa knockdown abrogated selinexor/ bortezomib-induced cytotoxicity in MM cells. Selinexor/ bortezomib treatment decreased NFkB transcriptional activity. Selinexor, when used with bortezomib or carfilzomib, has the potential to overcome PI drug resistance in MM. Sensitization may be due to inactivation of the NFkB pathway by IkBa.