title: A novel Bruton's tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib impacts the bone microenvironment in a multiple myeloma model with resultant antimyeloma activity.
abstract: Bruton's tyrosine kinase (Btk) modulates B-cell development and activation and has an important role in antibody production. Interestingly, Btk may also affect human osteoclast (OC) function; however, the mechanism was unknown. Here we studied a potent and specific Btk inhibitor, CC-292, in multiple myeloma (MM). In this report, we demonstrate that, although CC-292 increased OC differentiation, it inhibited OC function via inhibition of c-Src, Pyk2 and cortactin, all involved in OC-sealing zone formation. As CC-292 did not show potent in vitro anti-MM activity, we next evaluated it in combination with the proteasome inhibitor, carfilzomib. We first studied the effect of carfilzomib on OC. Carfilzomib did not have an impact on OC-sealing zone formation but significantly inhibited OC differentiation. CC-292 combined with carfilzomib inhibited both sealing zone formation and OC differentiation, resulting in more profound inhibition of OC function than carfilzomib alone. Moreover, the combination treatment in an in vivo MM mouse model inhibited tumor burden compared with CC-292 alone; it also increased bone volume compared with carfilzomib alone. These results suggest that CC-292 combined with carfilzomib augments the inhibitory effects against OC within the bone microenvironment and has promising therapeutic potential for the treatment of MM and related bone disease.
authors: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: H
authors: H
authors: Eda
authors: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: L
authors: L
authors: Santo
authors: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: D D
authors: DD
authors: Cirstea
authors: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: A J
authors: AJ
authors: Yee
authors: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: T A
authors: TA
authors: Scullen
authors: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: N
authors: N
authors: Nemani
authors: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: Y
authors: Y
authors: Mishima
authors: Massachusetts General Hospital Center for Systems Biology, Boston, MA, USA.
authors: P R
authors: PR
authors: Waterman
authors: Onyx Pharmaceuticals Inc., South San Francisco, CA, USA.
authors: S
authors: S
authors: Arastu-Kapur
authors: Celgene Avilomics Research, Bedford, MA, USA.
authors: E
authors: E
authors: Evans
authors: Celgene Avilomics Research, Bedford, MA, USA.
authors: J
authors: J
authors: Singh
authors: Onyx Pharmaceuticals Inc., South San Francisco, CA, USA.
authors: C J
authors: CJ
authors: Kirk
authors: Celgene Avilomics Research, Bedford, MA, USA.
authors: W F
authors: WF
authors: Westlin
authors: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
authors: N S
authors: NS
authors: Raje
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage* / Q000494:pharmacology; D000199:Actins / Q000037:antagonists & inhibitors; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001862:Bone Resorption / Q000517:prevention & control; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000008:administration & dosage*; D010010:Osteoclasts / Q000187:drug effects*; D061988:Proteasome Inhibitors / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000178:Acrylamides; D000199:Actins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D011743:Pyrimidines; C524865:carfilzomib; C583568:spebrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse