title: Synergistic Myeloma Cell Death via Novel Intracellular Activation of Caspase-10-Dependent Apoptosis by Carfilzomib and Selinexor.
abstract: Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line-derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers.
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Shaun
authors.initials: S
authors.lastname: Rosebeck
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Mattina M
authors.initials: MM
authors.lastname: Alonge
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Malathi
authors.initials: M
authors.lastname: Kandarpa
authors.affiliation: Computation Institute, University of Chicago, Chicago, Illinois.
authors.forename: Anoop
authors.initials: A
authors.lastname: Mayampurath
authors.affiliation: Computation Institute, University of Chicago, Chicago, Illinois.
authors.forename: Samuel L
authors.initials: SL
authors.lastname: Volchenboum
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Jagoda
authors.initials: J
authors.lastname: Jasielec
authors.affiliation: Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Dytfeld
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Maxwell
authors.affiliation: University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Kraftson
authors.affiliation: Karyopharm Therapeutics, Newton, Massachusetts.
authors.forename: Dilara
authors.initials: D
authors.lastname: McCauley
authors.affiliation: Karyopharm Therapeutics, Newton, Massachusetts.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Karyopharm Therapeutics, Newton, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois. ajakubowiak@medicine.bsd.uchicago.edu.
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Jakubowiak
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D053455:Caspase 10 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D042541:Intracellular Space; D051379:Mice; D009101:Multiple Myeloma / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006834:Hydrazines; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D014230:Triazoles; C585161:selinexor; C524865:carfilzomib; D053455:Caspase 10; D053181:Caspase 8