Inhibitory effects of the mitogen-activated protein kinase kinase inhibitor CI-1040 on the proliferation and tumor growth of thyroid cancer cells with BRAF or RAS mutations

J Clin Endocrinol Metab. 2007 Dec;92(12):4686-95. doi: 10.1210/jc.2007-0097. Epub 2007 Oct 2.


Context: Targeting MAPK kinase (MEK) in the MAPK pathway is a potentially effective therapeutic strategy for thyroid cancer.

Objective: The objective of the study was to investigate genotype-dependent therapeutic potential of the MEK inhibitor CI-1040 for thyroid cancer.

Experimental design: We examined the effects of CI-1040 on proliferation, apoptosis, transformation, thyroid gene reexpression, and xenograft tumor growth with respect to genotypes in 10 thyroid tumor cell lines.

Results: Cell proliferation was potently inhibited by CI-1040 in cells harboring BRAF or RAS mutations but not in cells harboring RET/PTC rearrangement or wild-type alleles. For example, the IC50 values for BRAF mutation-harboring KAT10 cells and DRO cells and H-RAS mutation-harboring C643 cells were 0.365, 0.031, and 0.429 microm, respectively, whereas the IC50 values for RET/PTC1-harboring TPC1 cells and the wild-type MRO and WRO cells were 44, 46, and 278 microm, respectively. Proapoptotic effect of CI-1040 was seen in DRO cells, and cytostatic effect was seen in other cells. Down-regulation of cyclin D1 and reexpression of some thyroid genes were induced by CI-1040 in some BRAF mutation-harboring cells, and transformation was inhibited in all cells. CI-1040 also inhibited the growth of xenograft tumors in nude mice derived from KAT10 or C643 cells but not that derived from MRO cells.

Conclusions: We for the first time demonstrated potent inhibitory effects of a MEK inhibitor, CI-1040, on thyroid cancer cells, some of which, particularly cell proliferation and tumor growth, seemed to be BRAF mutation or RAS mutation selective. Our data encourage a clinical trial on CI-1040 in thyroid cancer patients.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzamides / pharmacology*
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin D1 / biosynthesis
  • Cyclin D1 / genetics
  • DNA Fragmentation
  • Enzyme Inhibitors / pharmacology*
  • Genes, ras / genetics*
  • Humans
  • Hyperplasia / pathology
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mutation
  • Proto-Oncogene Proteins B-raf / genetics*
  • RNA / biosynthesis
  • RNA / isolation & purification
  • Thyroid Neoplasms / genetics*
  • Thyroid Neoplasms / pathology*
  • Xenograft Model Antitumor Assays


  • 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
  • Benzamides
  • Enzyme Inhibitors
  • Cyclin D1
  • RNA
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinase Kinases