Inhibition of the growth of papillary thyroid carcinoma cells by CI-1040.

Abstract

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.

• Authors: Ying C Henderson, Soon-Hyun Ahn, Gary L Clayman
• Journal: Archives of otolaryngology--head & neck surgery (Arch Otolaryngol Head Neck Surg) Vol. 135 Issue 4 Pg. 347-54 (Apr 2009) ISSN: 1538-361X [Electronic] United States
• PMID: 19380355 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
• Benzamides
• Enzyme Inhibitors
• Proto-Oncogene Proteins c-ret
• RET protein, human
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• MAP Kinase Kinase Kinase 1

Topics

• Animals
• Benzamides (pharmacology)
• Carcinoma, Papillary (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Gene Rearrangement
• MAP Kinase Kinase Kinase 1 (antagonists & inhibitors)
• Mice
• Mice, Nude
• Mutation
• Proto-Oncogene Proteins B-raf (genetics)
• Proto-Oncogene Proteins c-ret (genetics)
• Thyroid Neoplasms (drug therapy, genetics, pathology)