title: Dual inhibition of Mcl-1 by the combination of carfilzomib and TG02 in multiple myeloma.
abstract: Carfilzomib (Kyprolis®), a second generation proteasome inhibitor, is FDA approved for single-agent use among relapsed/refractory multiple myeloma (MM). To enhance the therapeutic efficacy of carfilzomib, we sought to combine carfilzomib with other novel agents. TG02, a multi-kinase inhibitor, targets JAK2 and CDK9. The rationale for co-treatment with carfilzomib and TG02 is that both independently target Mcl-1 and most myeloma cells are dependent on this anti-apoptotic protein for survival. We observed at least additive effects using the combination treatment in MM cell lines and patient samples. To determine how the bone marrow environment affects the efficacy of the combination we conducted co-culture experiments with Hs-5 stromal cells. We also examined the mechanism of increased apoptosis by determining the affect on expression of the Bcl-2 family of proteins. We found that carfilzomib increases NOXA mRNA expression, as expected, and TG02 treatment caused a decrease in Mcl-1 protein but not mRNA levels. Consistent with this possibility, we find silencing CDK9 does not change carfilzomib sensitivity in the same manner as addition of TG02. Since changes in Mcl-1 protein occur in the presence of a proteasome inhibitor we hypothesize that regulation of Mcl-1 translation is the most likely mechanism. Taken together our data suggest that dual inhibition of Mcl-1 via decreased expression and the induction of its antagonist NOXA by the combination of carfilzomib and TG02 is active in myeloma and warrants further testing preclinically and in clinical trials. Moreover, regulation of Mcl-1 by TG02 is more complex than initially appreciated.
authors.affiliation: a Cancer Biology Graduate Program , Winship Cancer Institute of Emory University , Atlanta , GA , USA.
authors.forename: Katelyn G
authors.initials: KG
authors.lastname: Ponder
authors.affiliation: b Department of Hematology and Medical Oncology , Winship Cancer Institute of Emory University , Atlanta , GA , USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Matulis
authors.affiliation: b Department of Hematology and Medical Oncology , Winship Cancer Institute of Emory University , Atlanta , GA , USA.
authors.forename: Sadae
authors.initials: S
authors.lastname: Hitosugi
authors.affiliation: b Department of Hematology and Medical Oncology , Winship Cancer Institute of Emory University , Atlanta , GA , USA.
authors.forename: Vikas A
authors.initials: VA
authors.lastname: Gupta
authors.affiliation: c Winship Cancer Institute of Emory University , Atlanta , GA , USA.
authors.forename: Cathy
authors.initials: C
authors.lastname: Sharp
authors.affiliation: d Tragara Pharmaceuticals , San Diego , CA , USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Burrows
authors.affiliation: b Department of Hematology and Medical Oncology , Winship Cancer Institute of Emory University , Atlanta , GA , USA.|c Winship Cancer Institute of Emory University , Atlanta , GA , USA.
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Nooka
authors.affiliation: b Department of Hematology and Medical Oncology , Winship Cancer Institute of Emory University , Atlanta , GA , USA.|c Winship Cancer Institute of Emory University , Atlanta , GA , USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Kaufman
authors.affiliation: b Department of Hematology and Medical Oncology , Winship Cancer Institute of Emory University , Atlanta , GA , USA.|c Winship Cancer Institute of Emory University , Atlanta , GA , USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.affiliation: b Department of Hematology and Medical Oncology , Winship Cancer Institute of Emory University , Atlanta , GA , USA.|c Winship Cancer Institute of Emory University , Atlanta , GA , USA.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C570909:14-methyl-20-oxa-5,7,14,26-tetraazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8(27),9,11,16,21,23-decaene; D006576:Heterocyclic Compounds, 4 or More Rings; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009842:Oligopeptides; C524865:carfilzomib
keywords: Apoptosis; Bcl-2; plasma cell dyscrasia