title: The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel.
abstract: OBJECTIVE
  Disseminated melanoma is highly therapy resistant. The finding that 66% of melanomas harbor the activating BRAF(V600E) mutation has raised expectations for targeting the Ras/RAF/mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway in melanoma. This study addresses the anti-melanoma activity of the MEK inhibitor AZD6244 (ARRY-142886).
  
  
  METHODS
  We recently have shown that growing melanoma cells as three-dimensional collagen-implanted spheroids enhances resistance to the MEK inhibitor U0126. Here, we investigated the anti-melanoma activity of AZD6244 in two-dimensional cell culture, the three-dimensional spheroid model, and an in vivo model.
  
  
  RESULTS
  In two-dimensional cell culture, AZD6244 was cytostatic and reduced the growth of melanoma cells in a concentration-dependent fashion through the induction of G(1)-phase cell cycle arrest. In our three-dimensional spheroid model, the effects of AZD6244 were largely cytostatic and reversible, with drug washout leading to spheroid regrowth. Finally, 1205Lu cells were grown as tumor xenografts in severe combined immunodeficient mice. After tumor establishment, mice were dosed twice daily with 0, 10, or 30 mg/kg AZD6244 p.o. AZD6244 treatment decreased phospho-ERK in the tumors and significantly suppressed tumor growth. The original tumors remained viable, suggesting that AZD6244 monotherapy was largely cytostatic, and not proapoptotic in this model. Further studies showed that co-administration of AZD6244 (30 mg/kg) with docetaxel (15 mg/kg) led to tumor regression, indicating the potential for MEK inhibitor/chemotherapy drug combinations.
  
  
  CONCLUSIONS
  Inhibition of MEK is cytostatic as a monotherapy in melanoma, but cytotoxic when combined with docetaxel.
authors.affiliation: The Wistar Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Nikolas K
authors.initials: NK
authors.lastname: Haass
authors.forename: Katrin
authors.initials: K
authors.lastname: Sproesser
authors.forename: Thiennga K
authors.initials: TK
authors.lastname: Nguyen
authors.forename: Rooha
authors.initials: R
authors.lastname: Contractor
authors.forename: C Angelica
authors.initials: CA
authors.lastname: Medina
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.forename: Keiran S M
authors.initials: KS
authors.lastname: Smalley
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D054697:Cytostatic Agents / Q000008:administration & dosage; D003603:Cytotoxins / Q000008:administration & dosage; D000077143:Docetaxel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D006801:Humans; D020287:In Situ Nick-End Labeling; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology; D051379:Mice; D016513:Mice, SCID; D009693:Nucleic Acid Hybridization; D043823:Taxoids / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D054697:Cytostatic Agents; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D048049:Extracellular Signal-Regulated MAP Kinases