BRAFV600E Mutation Is Associated with Preferential Sensitivity to Mitogen-Activated Protein Kinase Kinase Inhibition in Thyroid Cancer Cell Lines

• Published in: The journal of clinical endocrinology and metabolism 2008-06, Vol.93 (6), p.2194-2201
• Main Authors: Leboeuf, Rebecca, Baumgartner, Jacqueline E., Benezra, Miriam, Malaguarnera, Roberta, Solit, David, Pratilas, Christine A., Rosen, Neal, Knauf, Jeffrey A., Fagin, James A.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Benzamides - pharmacology; Benzimidazoles - pharmacology; Biological and medical sciences; Carcinoma - enzymology; Carcinoma - genetics; Cell Line, Tumor; Cell Proliferation - drug effects; Diphenylamine - analogs & derivatives; Diphenylamine - pharmacology; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Endocrinopathies; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Humans; Malignant tumors; Medical sciences; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mutation, Missense; Original; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - genetics; Substrate Specificity; Thyroid Neoplasms - enzymology; Thyroid Neoplasms - genetics; Thyroid. Thyroid axis (diseases); Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Xenograft Model Antitumor Assays
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2007-2825

Context: Mutually exclusive mutations of RET, RAS, or BRAF are present in about 70% of papillary thyroid carcinomas, whereas only the latter two are seen in poorly differentiated and anaplastic cancers. Although the signal output common to these oncoproteins is ERK, a recent report showed that only BRAF mutations consistently predicted responsiveness to MAPK kinase (MEK) inhibitors. Objectives: Here we investigated whether sensitivity to MEK inhibition was determined by oncogene status in 13 human thyroid cancer cell lines: four with BRAF mutations, four RAS, one RET/PTC1, and four wild type. Results: Growth of BRAF (+) cells was inhibited by the MEK antagonist PD0325901 with an IC50 of less than 5 nm. By contrast, RAS, RET/PTC1, or wild-type cells had IC50 of 4 nm to greater than 1000nm. Sensitivity was not predicted by coexisting mutations in PIK3CA or by PTEN status. Similar effects were obtained with the MEK inhibitor AZD6244. PD0325901 induced a sustained G1/S arrest in BRAF (+) but not BRAF (−) lines. PD0325901 was equipotent at inhibiting pERK1/2 after 2 h, regardless of genetic background, but pERK rebounded at 24 h in most lines. MEK inhibitor resistance was associated with partial refractoriness of pERK to further inhibition by the compounds. AZD6244 was more potent at inhibiting growth of NPA (BRAF +) than Cal62 (KRAS +) xenografts. Conclusion: Thyroid cancers with BRAF mutation are preferentially sensitive to MEK inhibitors, whereas tumors with other MEK-ERK effector pathway gene mutations have variable responses, either because they are only partially dependent on ERK and/or because feedback responses elicit partial refractoriness to MEK inhibition.