azd-6244 and perifosine

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.

Topics: 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

The purpose of the study was to explore optimal combinations of currently actively developed drugs for dually targeting the Ras → Raf → MAPK kinase (MEK) → MAPK/ERK (MAPK) and the phosphatidylinositol 3-kinase/Akt pathways as effective treatments for thyroid cancer.. We tested the combinations of the Akt inhibitors MK2206 or perifosine with the BRAF(V600E) inhibitor PLX4032 or the MEK1/2 inhibitor AZD6244 in thyroid cancer cells harboring both the BRAF(V600E) and PIK3CA mutations.. We found that MK2206 could potently, when used alone, and synergistically, when combined with either PLX4032 or AZD6244, inhibit thyroid cancer cell growth with all the combination index values lower than 1. Perifosine could potently inhibit thyroid cancer cell growth when used alone, but a strong antagonism occurred between this drug and PLX4032 or AZD6244 in the inhibition of thyroid cancer cell growth with all combination index values higher than 1. Combinations of MK2206 with PLX4032 or AZD6244 dramatically enhanced G1 cell cycle arrest induced by each drug alone. However, G2 cell cycle arrest uniquely induced by perifosine alone and G1 cell cycle arrest induced by PLX4032 or AZD6244 were both reversed by combination treatments, providing a mechanism for their antagonism. All these drugs could correspondingly inhibit the MAPK and phosphatidylinositol 3-kinase/Akt signalings, confirming their expected target effects.. We demonstrated, unexpectedly, opposite outcomes of MK2206 and perifosine in their combinational treatments with BRAF(V600E)/MEK inhibitors in thyroid cancer cells. The data may help appropriate selection of these prominent drugs for clinical trials of combination therapies for thyroid cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carcinoma; Cell Proliferation; Down-Regulation; Drug Antagonism; Drug Evaluation, Preclinical; Drug Synergism; Glutamic Acid; Heterocyclic Compounds, 3-Ring; Humans; Indoles; Mutant Proteins; Oncogene Protein v-akt; Phosphorylcholine; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Sulfonamides; Thyroid Neoplasms; Tumor Cells, Cultured; Valine; Vemurafenib