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

Dingxie Liu, Zhi Liu, David Jiang, Alan P. Dackiw, Michael Mingzhao Xing

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Abstract

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 μM, respectively, whereas the IC 50 values for RET/PTC1-harboring TPC1 cells and the wild-type MRO and WRO cells were 44, 46, and 278 μM, 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.

Original languageEnglish (US)
Pages (from-to)4686-4695
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume92
Issue number12
DOIs
StatePublished - Dec 2007

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Mitogen-Activated Protein Kinase Kinases
Thyroid Neoplasms
Tumors
Cells
Mutation
Growth
Neoplasms
Cell proliferation
Heterografts
Genes
Thyroid Gland
Factor IX
2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
Cyclin D1
Cytostatic Agents
Design of experiments
Genotype
Cell Proliferation
Apoptosis
Tumor Cell Line

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

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. / Liu, Dingxie; Liu, Zhi; Jiang, David; Dackiw, Alan P.; Xing, Michael Mingzhao.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 92, No. 12, 12.2007, p. 4686-4695.

Research output: Contribution to journalArticle

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abstract = "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 μM, respectively, whereas the IC 50 values for RET/PTC1-harboring TPC1 cells and the wild-type MRO and WRO cells were 44, 46, and 278 μM, 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.",
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AU - Dackiw, Alan P.

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N2 - 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 μM, respectively, whereas the IC 50 values for RET/PTC1-harboring TPC1 cells and the wild-type MRO and WRO cells were 44, 46, and 278 μM, 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.

AB - 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 μM, respectively, whereas the IC 50 values for RET/PTC1-harboring TPC1 cells and the wild-type MRO and WRO cells were 44, 46, and 278 μM, 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.

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