XPO1 inhibitor combination therapy with bortezomib or carfilzomib induces nuclear localization of IκBα 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 NFκB pathway protein expression assays, immunofluorescence microscopy, ImageStream flow-cytometry, and proximity-ligation assays. IκBα knockdown and NFκB 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 IκBα by selinexor/bortezomib. Proximity ligation found increased IκBα-NFκB complexes in treated MM cells. IκBα knockdown abrogated selinexor/bortezomib-induced cytotoxicity in MM cells. Selinexor/bortezomib treatment decreased NFκB 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 NFκB pathway by IκBα.
Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Joel G
JG
Turner
Karyopharm Therapeutics, Natick, MA, USA.
Trinayan
T
Kashyap
Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Jana L
JL
Dawson
Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Juan
J
Gomez
Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Alexis A
AA
Bauer
Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
Steven
S
Grant
Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
Yun
Y
Dai
Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.|Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Kenneth H
KH
Shain
Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Mark
M
Meads
Karyopharm Therapeutics, Natick, MA, USA.
Yosef
Y
Landesman
Chemical Biology and Molecular Medicine Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.|Department of Blood & Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Daniel M
DM
Sullivan
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000069286:Bortezomib / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
D000069286:Bortezomib; D006834:Hydrazines; D028884:Karyopherins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D009842:Oligopeptides; D046988:Proteasome Endopeptidase Complex; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C000606204:NFKBIA protein, human; C585161:selinexor; C524865:carfilzomib
XPO1; acquired drug resistance; bortezomib; carfilzomib; multiple myeloma