Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244

Douglas W. Ball, Ning Jin, D. Marc Rosen, Alan Dackiw, David Sidransky, Mingzhao Xing, Barry D. Nelkin

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Context: Activating mutations in the BRAF gene, primarily at V600E, are associated with poorer outcomes in patients with papillary thyroid cancer. MAPK kinase (MEK), immediately downstream of BRAF, is a promising target for ras-raf-MEK-ERK pathway inhibition. Objective: The objective of the investigation was to study the efficacy of a MEK1/2 inhibitor in thyroid cancer preclinical models with defined BRAF mutation status. Experimental Design: After treatment with the potent MEK 1/2 inhibitor AZD6244, MEK inhibition and cell growth were examined in four BRAF mutant (V600E) and two BRAF wild-type thyroid cancer cell lines and in xenografts from a BRAF mutant cell line. Results: AZD6244 potently inhibited MEK 1/2 activity in thyroid cancer cell lines regardless of BRAF mutation status, as evidenced by reduced ERK phosphorylation. Four BRAF mutant lines exhibited growth inhibition at low doses of the drug, with GI50 concentrations ranging from 14 to 50 nM, predominantly via a G0/G1 arrest, comparable with findings in a sensitive BRAF mutant melanoma cell line. In contrast, two BRAF wild-type lines were significantly less sensitive, with GI50 values greater than 200 nM. Nude mouse xenograft tumors derived from the BRAF mutant line ARO exhibited dose-dependent growth inhibition by AZD6244, with effective treatment at 10 mg/kg by oral gavage. This effect was primarily cytostatic and associated with marked inhibition of ERK phosphorylation. Conclusion: AZD6244 inhibits the MEK-ERK pathway across a spectrum of thyroid cancer cells. MEK inhibition is cytostatic in papillary thyroid cancer and anaplastic thyroid cancer cells bearing a BRAF mutation and may have less impact on thyroid cancer cells lacking this mutation.

Original languageEnglish (US)
Pages (from-to)4712-4718
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume92
Issue number12
DOIs
StatePublished - Dec 2007

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MAP Kinase Kinase 2
MAP Kinase Kinase 1
Mitogen-Activated Protein Kinase Kinases
Thyroid Neoplasms
Cells
Growth
Mutation
Cell Line
MAP Kinase Signaling System
Cytostatic Agents
Heterografts
Phosphorylation
Bearings (structural)
Nude Mice
AZD 6244
Melanoma
Cell growth
Research Design
Design of experiments
Tumors

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244. / Ball, Douglas W.; Jin, Ning; Rosen, D. Marc; Dackiw, Alan; Sidransky, David; Xing, Mingzhao; Nelkin, Barry D.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 92, No. 12, 12.2007, p. 4712-4718.

Research output: Contribution to journalArticle

Ball, Douglas W. ; Jin, Ning ; Rosen, D. Marc ; Dackiw, Alan ; Sidransky, David ; Xing, Mingzhao ; Nelkin, Barry D. / Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244. In: Journal of Clinical Endocrinology and Metabolism. 2007 ; Vol. 92, No. 12. pp. 4712-4718.
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AU - Rosen, D. Marc

AU - Dackiw, Alan

AU - Sidransky, David

AU - Xing, Mingzhao

AU - Nelkin, Barry D.

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