title: CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications.
abstract: The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50<200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Y-T
authors.initials: YT
authors.lastname: Tai
authors.affiliation: Department of Biology, Karyopharm Therapeutics Inc, Natick, MA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Landesman
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Acharya
authors.affiliation: Department of Haematological Medicine, King's College London, London, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Calle
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: M Y
authors.initials: MY
authors.lastname: Zhong
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cea
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Tannenbaum
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Cagnetta
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Reagan
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Munshi
authors.affiliation: Department of Biology, Karyopharm Therapeutics Inc, Natick, MA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Senapedis
authors.affiliation: Department of Biology, Karyopharm Therapeutics Inc, Natick, MA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Saint-Martin
authors.affiliation: Department of Biology, Karyopharm Therapeutics Inc, Natick, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kashyap
authors.affiliation: Department of Biology, Karyopharm Therapeutics Inc, Natick, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Department of Biology, Karyopharm Therapeutics Inc, Natick, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kauffman
authors.affiliation: Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wu
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Ghobrial
authors.affiliation: Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Zhan
authors.affiliation: Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: Lurie Family Imaging Center, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Schey
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Richardson
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: N C
authors.initials: NC
authors.lastname: Munshi
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: K C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D006801:Humans; D028884:Karyopherins / Q000037:antagonists & inhibitors*; D009101:Multiple Myeloma / Q000473:pathology / Q000628:therapy*; D010010:Osteoclasts / Q000473:pathology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D000097606:Exportin 1 Protein
chemical_list: D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein