BRAFV600E mutation is associated with preferential sensitivity to mitogen-activated protein kinase kinase inhibition in thyroid cancer cell lines

Rebecca Leboeuf, Jacqueline E. Baumgartner, Miriam Benezra, Roberta Malaguarnera, David Solit, Christine Pratilas, Neal Rosen, Jeffrey A. Knauf, James A. Fagin

Research output: Contribution to journalArticle

Abstract

Context: Mutually exclusive mutations of RET, RAS, or BRAF are present in about 70% of papillary thyroid carcinomas, whereas only the latter two are seen in poorly differentiated and anaplastic cancers. Although the signal output common to these oncoproteins is ERK, a recent report showed that only BRAF mutations consistently predicted responsiveness to MAPK kinase (MEK) inhibitors. Objectives: Here we investigated whether sensitivity to MEK inhibition was determined by oncogene status in 13 human thyroid cancer cell lines: four with BRAF mutations, four RAS, one RET/ PTC1, and four wild type. Results: Growth of BRAF (+) cells was inhibited by the MEK antagonist PD0325901 with an IC 50 of less than 5nM. By contrast, RAS, RET/PTC1, or wild-type cells had IC50 of 4 nM to greater than 1000nM. Sensitivity was not predicted by coexisting mutations in PIK3CA or by PTEN status. Similar effects were obtained with the MEK inhibitor AZD6244. PD0325901 induced a sustained G1/S arrest in BRAF (+) but not BRAF (-) lines. PD0325901 was equipotent at inhibiting pERK1/2 after 2 h, regardless of genetic background, but pERK rebounded at 24 h in most lines. MEK inhibitor resistance was associated with partial refractoriness of pERK to further inhibition by the compounds. AZD6244 was more potent at inhibiting growth of NPA (BRAF +) than Cal62 (KRAS +) xenografts. Conclusion: Thyroid cancers with BRAF mutation are preferentially sensitive to MEK inhibitors, whereas tumors with other MEK-ERK effector pathway gene mutations have variable responses, either because they are only partially dependent on ERK and/or because feedback responses elicit partial refractoriness to MEK inhibition.

Original languageEnglish (US)
Pages (from-to)2194-2201
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Volume93
Issue number6
DOIs
StatePublished - Jun 2008
Externally publishedYes

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Mitogen-Activated Protein Kinase Kinases
Thyroid Neoplasms
Cells
Cell Line
Mutation
MAP Kinase Signaling System
Oncogene Proteins
Growth
Oncogenes
Heterografts
Inhibitory Concentration 50
Neoplasms
Tumors
Genes
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ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

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BRAFV600E mutation is associated with preferential sensitivity to mitogen-activated protein kinase kinase inhibition in thyroid cancer cell lines. / Leboeuf, Rebecca; Baumgartner, Jacqueline E.; Benezra, Miriam; Malaguarnera, Roberta; Solit, David; Pratilas, Christine; Rosen, Neal; Knauf, Jeffrey A.; Fagin, James A.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 93, No. 6, 06.2008, p. 2194-2201.

Research output: Contribution to journalArticle

Leboeuf, Rebecca ; Baumgartner, Jacqueline E. ; Benezra, Miriam ; Malaguarnera, Roberta ; Solit, David ; Pratilas, Christine ; Rosen, Neal ; Knauf, Jeffrey A. ; Fagin, James A. / BRAFV600E mutation is associated with preferential sensitivity to mitogen-activated protein kinase kinase inhibition in thyroid cancer cell lines. In: Journal of Clinical Endocrinology and Metabolism. 2008 ; Vol. 93, No. 6. pp. 2194-2201.
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T1 - BRAFV600E mutation is associated with preferential sensitivity to mitogen-activated protein kinase kinase inhibition in thyroid cancer cell lines

AU - Leboeuf, Rebecca

AU - Baumgartner, Jacqueline E.

AU - Benezra, Miriam

AU - Malaguarnera, Roberta

AU - Solit, David

AU - Pratilas, Christine

AU - Rosen, Neal

AU - Knauf, Jeffrey A.

AU - Fagin, James A.

PY - 2008/6

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N2 - Context: Mutually exclusive mutations of RET, RAS, or BRAF are present in about 70% of papillary thyroid carcinomas, whereas only the latter two are seen in poorly differentiated and anaplastic cancers. Although the signal output common to these oncoproteins is ERK, a recent report showed that only BRAF mutations consistently predicted responsiveness to MAPK kinase (MEK) inhibitors. Objectives: Here we investigated whether sensitivity to MEK inhibition was determined by oncogene status in 13 human thyroid cancer cell lines: four with BRAF mutations, four RAS, one RET/ PTC1, and four wild type. Results: Growth of BRAF (+) cells was inhibited by the MEK antagonist PD0325901 with an IC 50 of less than 5nM. By contrast, RAS, RET/PTC1, or wild-type cells had IC50 of 4 nM to greater than 1000nM. Sensitivity was not predicted by coexisting mutations in PIK3CA or by PTEN status. Similar effects were obtained with the MEK inhibitor AZD6244. PD0325901 induced a sustained G1/S arrest in BRAF (+) but not BRAF (-) lines. PD0325901 was equipotent at inhibiting pERK1/2 after 2 h, regardless of genetic background, but pERK rebounded at 24 h in most lines. MEK inhibitor resistance was associated with partial refractoriness of pERK to further inhibition by the compounds. AZD6244 was more potent at inhibiting growth of NPA (BRAF +) than Cal62 (KRAS +) xenografts. Conclusion: Thyroid cancers with BRAF mutation are preferentially sensitive to MEK inhibitors, whereas tumors with other MEK-ERK effector pathway gene mutations have variable responses, either because they are only partially dependent on ERK and/or because feedback responses elicit partial refractoriness to MEK inhibition.

AB - Context: Mutually exclusive mutations of RET, RAS, or BRAF are present in about 70% of papillary thyroid carcinomas, whereas only the latter two are seen in poorly differentiated and anaplastic cancers. Although the signal output common to these oncoproteins is ERK, a recent report showed that only BRAF mutations consistently predicted responsiveness to MAPK kinase (MEK) inhibitors. Objectives: Here we investigated whether sensitivity to MEK inhibition was determined by oncogene status in 13 human thyroid cancer cell lines: four with BRAF mutations, four RAS, one RET/ PTC1, and four wild type. Results: Growth of BRAF (+) cells was inhibited by the MEK antagonist PD0325901 with an IC 50 of less than 5nM. By contrast, RAS, RET/PTC1, or wild-type cells had IC50 of 4 nM to greater than 1000nM. Sensitivity was not predicted by coexisting mutations in PIK3CA or by PTEN status. Similar effects were obtained with the MEK inhibitor AZD6244. PD0325901 induced a sustained G1/S arrest in BRAF (+) but not BRAF (-) lines. PD0325901 was equipotent at inhibiting pERK1/2 after 2 h, regardless of genetic background, but pERK rebounded at 24 h in most lines. MEK inhibitor resistance was associated with partial refractoriness of pERK to further inhibition by the compounds. AZD6244 was more potent at inhibiting growth of NPA (BRAF +) than Cal62 (KRAS +) xenografts. Conclusion: Thyroid cancers with BRAF mutation are preferentially sensitive to MEK inhibitors, whereas tumors with other MEK-ERK effector pathway gene mutations have variable responses, either because they are only partially dependent on ERK and/or because feedback responses elicit partial refractoriness to MEK inhibition.

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