title: GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment.
abstract: Previous studies have shown that the multiple myeloma (MM) cell line and MM patient cells express high-affinity vascular endothelial growth factor (VEGF) receptor-1 or Fms-like tyrosine kinase-1 (Flt-1) but not VEGF receptor-2 or Flk-1/kinase insert domain-containing receptor (Flk-1/KDR) and that VEGF triggers MM cell proliferation through a mitogen-activated protein kinase (MAPK)-dependent pathway and migration through a protein kinase C (PKC)-dependent pathway. The present study evaluates the efficacy of the small molecule tyrosine-kinase inhibitor GW654652, which inhibits all 3 VEGF receptors with similar potency. We show that GW654652 acts directly on MM cells and in the bone marrow microenvironment. Specifically, GW654652 (1-10 microg/mL) inhibits, in a dose-dependent fashion, VEGF-triggered migrational activity and cell proliferation of MM cell lines that are sensitive and resistant to conventional therapy. As expected from our previous studies of VEGF-induced signaling and sequelae in MM cells, GW654652 blocked VEGF-induced Flt-1 phosphorylation and downstream activation of AKT-1 and MAPK-signaling cascades. Importantly, GW654652 also inhibits interleukin-6 and VEGF secretion and proliferation of MM cells induced by tumor cell binding to bone marrow (BM) stromal cells. The activity of a pan-VEGF receptor inhibitor against MM cells in the BM milieu, coupled with its lack of major toxicity in preclinical mouse models, provides the framework for clinical trials of this drug class to improve patient outcome in MM.
authors.affiliation: Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.forename: Laurence P
authors.initials: LP
authors.lastname: Catley
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Reshma
authors.initials: R
authors.lastname: Shringarpure
authors.forename: Pedro
authors.initials: P
authors.lastname: Carvalho
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hayashi
authors.forename: Renate
authors.initials: R
authors.lastname: Burger
authors.forename: Robert L
authors.initials: RL
authors.lastname: Schlossman
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Lini N
authors.initials: LN
authors.lastname: Pandite
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D001853:Bone Marrow / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C486980:GW 654652; D007093:Imidazoles; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt