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.
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.
Haass
Nikolas K
NK
The Wistar Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Sproesser
Katrin
K
Nguyen
Thiennga K
TK
Contractor
Rooha
R
Medina
C Angelica
CA
Nathanson
Katherine L
KL
Herlyn
Meenhard
M
Smalley
Keiran S M
KS
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
C517975:AZD 6244; D001562:Benzimidazoles; D054697:Cytostatic Agents; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D048049:Extracellular Signal-Regulated MAP Kinases