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9935823 
Journal Article 
Inhibition of the growth of papillary thyroid carcinoma cells by CI-1040 
Henderson, YC; Ahn, SH; Clayman, GL 
2009 
Yes 
Archives of Otolaryngology - Head and Neck Surgery
ISSN: 0886-4470
EISSN: 1538-361X 
135 
4 
347-354 
English 
19380355 
BACKGROUND: Papillary thyroid carcinoma (PTC), the most common type of thyroid malignancy, usually possesses mutations, either RET/PTC rearrangement or BRAF mutation. Both mutations can activate the mitogen-activated protein kinase kinase/extracellular signal-related kinase signaling transduction pathway, which results in activation of transcription factors that regulate cellular proliferation, differentiation, and apoptosis.

OBJECTIVE: To test the effects of CI-1040 (PD184352), a specific MEK1/2 inhibitor, on PTC cells carrying either an RET/PTC1 rearrangement or a BRAF mutation.

DESIGN: The effects of CI-1040 on PTC cells were evaluated in vitro and in vivo.

MAIN OUTCOME MEASURES: The effects of CI-1040 on PTC cells were evaluated in vitro using a cell proliferation assay, cell cycle analysis, and immunoblotting. The antitumor effects of CI-1040 in vivo were evaluated in an orthotopic mouse model.

RESULTS: The concentrations of CI-1040 needed to inhibit 50% cell growth were 0.052microM for PTC cells with a BRAF mutation and 1.1microM for PTC cells with the RET/PTC1 rearrangement. After 3 weeks of oral administration of CI-1040 (300 mg/kg/d) to mice with orthotopic tumor implants of PTC cells, the mean tumor volume of implants bearing the RET/PTC1 rearrangement (n = 5) was reduced 47.5% compared with untreated mice (from 701.9 to 368.5 mm(3)), and the mean volume of implants with a BRAF mutation (n = 8) was reduced 31.3% (from 297.3 to 204.2 mm(3)).

CONCLUSIONS: CI-1040 inhibits PTC cell growth in vitro and in vivo. Because RET/PTC rearrangements are unique to thyroid carcinomas and a high percentage of PTCs possess either mutation, these findings support the clinical evaluation of CI-1040 for patients with PTC.