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Selective Growth Inhibition in BRAF Mutant Thyroid Cancer by the Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (D.W.B., N.J., D.M.R., D.S., M.X., B.D.N.), Division of Endocrinology and Metabolism (D.W.B., M.X.), Department of Surgery (A.D.), and Department of Otolaryngology-Head and Neck Surgery (D.S.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Address all correspondence and requests for reprints to: Douglas W. Ball, M.D., Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 553, Baltimore, Maryland 21231-1000. E-mail: dball{at}jhmi.edu.

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.

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