Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis.
Activation of the extracellular signal-regulated kinase1/2 (ERK1/2) signaling cascade mediates human multiple myeloma (MM) growth and survival triggered by cytokines and adhesion to bone marrow stromal cells (BMSCs). Here, we examined the effect of AZD6244 (ARRY-142886), a novel and specific MEK1/2 inhibitor, on human MM cell growth in the bone marrow (BM) milieu. AZD6244 blocks constitutive and cytokine-stimulated ERK1/2 phosphorylation and inhibits proliferation and survival of human MM cell lines and patient MM cells, regardless of sensitivity to conventional chemotherapy. Importantly, AZD6244 (200 nM) induces apoptosis in patient MM cells, even in the presence of exogenous interleukin-6 or BMSCs associated with triggering of caspase 3 activity. AZD6244 sensitizes MM cells to both conventional (dexamethasone) and novel (perifosine, lenalidomide, and bortezomib) therapies. AZD6244 down-regulates the expression/secretion of osteoclast (OC)-activating factors from MM cells and inhibits in vitro differentiation of MM patient PBMCs to OCs induced by ligand for receptor activator of NF-kappaB (RANKL) and macrophage-colony stimulating factor (M-CSF). Finally, AZD6244 inhibits tumor growth and prolongs survival in vivo in a human plasmacytoma xenograft model. Taken together, these results show that AZD6244 targets both MM cells and OCs in the BM microenvironment, providing the preclinical framework for clinical trials to improve patient outcome in MM.
Tai
Yu-Tzu
YT
The Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. yu-tzu_tai@dfci.harvard.edu
Fulciniti
Mariateresa
M
Hideshima
Teru
T
Song
Weihua
W
Leiba
Merav
M
Li
Xian-Feng
XF
Rumizen
Matthew
M
Burger
Peter
P
Morrison
Aileen
A
Podar
Klaus
K
Chauhan
Dharminder
D
Tassone
Pierfrancesco
P
Richardson
Paul
P
Munshi
Nikhil C
NC
Ghobrial
Irene M
IM
Anderson
Kenneth C
KC
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000201:enzymology / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000494:pharmacology* / Q000627:therapeutic use; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D015850:Interleukin-6 / Q000494:pharmacology; D000077269:Lenalidomide; D008024:Ligands; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000201:enzymology* / Q000473:pathology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D053245:RANK Ligand; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C517975:AZD 6244; D001562:Benzimidazoles; D001897:Boronic Acids; D003603:Cytotoxins; C508600:IL6 protein, human; D015850:Interleukin-6; D008024:Ligands; D011719:Pyrazines; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D010767:Phosphorylcholine; C105905:perifosine; D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; D016173:Macrophage Colony-Stimulating Factor; C482128:MAP2K2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D000077269:Lenalidomide