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Ying C. Henderson, MD, PhD; Soon-Hyun Ahn, MD; Gary L. Clayman, DDS, MD

Arch Otolaryngol Head Neck Surg. 2009;135(4):347-354.

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 0.052µM for PTC cells with a BRAF mutation and 1.1µM 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 mm³), and the mean volume of implants with a BRAF mutation (n = 8) was reduced 31.3% (from 297.3 to 204.2 mm³).

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.

Author Affiliations: Departments of Head and Neck Surgery (Drs Henderson, Ahn, and Clayman) and Cancer Biology (Dr Clayman), The University of Texas M. D. Anderson Cancer Center, Houston.

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