Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis.

Tai YT, Fulciniti M, Hideshima T, Song W, Leiba M, Li XF, Rumizen M, Burger P, Morrison A, Podar K, Chauhan D, Tassone P, Richardson P, Munshi NC, Ghobrial IM, Anderson KC
Blood. 2007 110 (5): 1656-63

PMID: 17510321 · PMCID: PMC1975848 · DOI:10.1182/blood-2007-03-081240

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.

MeSH Terms (35)

Animals Antineoplastic Combined Chemotherapy Protocols Benzimidazoles Bone Marrow Cells Boronic Acids Bortezomib Cell Adhesion Cell Differentiation Cell Proliferation Cell Survival Cytotoxins Dexamethasone Dose-Response Relationship, Drug Interleukin-6 Lenalidomide Ligands Macrophage Colony-Stimulating Factor MAP Kinase Kinase 1 MAP Kinase Kinase 2 MAP Kinase Signaling System Mice Mice, SCID Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Multiple Myeloma Neoplasm Transplantation Osteoclasts Phosphorylcholine Pyrazines RANK Ligand Stromal Cells Thalidomide Transplantation, Heterologous Tumor Cells, Cultured Xenograft Model Antitumor Assays

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