title: Targeting MEK1/2 blocks osteoclast differentiation, function and cytokine secretion in multiple myeloma.
abstract: Osteolytic bone disease in multiple myeloma (MM) is associated with upregulation of osteoclast (OCL) activity and constitutive inhibition of osteoblast function. The extracellular signal-regulated kinase 1/2 (ERK1/2) pathway mediates OCL differentiation and maturation. We hypothesized that inhibition of ERK1/2 could prevent OCL differentiation and downregulate OCL function. It was found that AZD6244, a mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, blocked OCL differentiation and formation in a dose-dependent manner, evidenced by decreased alphaVbeta3-integrin expression and tartrate-resistant acid phosphatase positive (TRAP+) cells. Functional dentine disc cultures showed inhibition of OCL-induced bone resorption by AZD6244. Major MM growth and survival factors produced by OCLs including B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL), as well as macrophage inflammatory protein (MIP-1alpha), which mediates OCL differentiation and MM, were also significantly inhibited by AZD6244. In addition to ERK inhibition, NFATc1 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1) and c-fos were both downregulated, suggesting that AZD6244 targets a later stage of OCL differentiation. These results indicate that AZD6244 inhibits OCL differentiation, formation and bone resorption, thereby abrogating paracrine MM cell survival in the bone marrow microenvironment. The present study therefore provides a preclinical rationale for the evaluation of AZD6244 as a potential new therapy for patients with MM.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Iris
authors.initials: I
authors.lastname: Breitkreutz
authors.forename: Marc S
authors.initials: MS
authors.lastname: Raab
authors.forename: Sonia
authors.initials: S
authors.lastname: Vallet
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D001562:Benzimidazoles / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western / Q000379:methods; D001862:Bone Resorption / Q000188:drug therapy; D002454:Cell Differentiation / Q000187:drug effects; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines / Q000378:metabolism; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D053245:RANK Ligand / Q000378:metabolism / Q000494:pharmacology; D000071681:Tartrate-Resistant Acid Phosphatase; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D015415:Biomarkers; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D004791:Enzyme Inhibitors; D039302:Integrin alphaVbeta3; D007527:Isoenzymes; D019402:Macrophage Inflammatory Proteins; D053245:RANK Ligand; D014157:Transcription Factors; D016173:Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase