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

Haass, Nikolas K., Sproesser, Katrin, Nguyen, Thiennga K., Contractor, Rooha, Medina, C. Angelica, Nathanson, Katherine L., Herlyn, Meenhard and Smalley, Keiran S. M. (2008) 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. Clinical Cancer Research, 14 1: 230-239. doi:10.1158/1078-0432.CCR-07-1440


Author Haass, Nikolas K.
Sproesser, Katrin
Nguyen, Thiennga K.
Contractor, Rooha
Medina, C. Angelica
Nathanson, Katherine L.
Herlyn, Meenhard
Smalley, Keiran S. M.
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
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1078-0432
1557-3265
Publication date 2008-01-01
Year available 2008
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-07-1440
Volume 14
Issue 1
Start page 230
End page 239
Total pages 10
Place of publication Philadelphia, PA United States
Publisher American Association for Cancer Research
Collection year 2009
Language eng
Subject 1306 Cancer Research
2730 Oncology
Abstract Purpose: 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). Experimental Design: 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 amonotherapy in melanoma, but cytotoxic when combined with docetaxel.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 163 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 173 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Sat, 31 May 2014, 04:03:56 EST by Nikolas Haass on behalf of UQ Diamantina Institute