Cytostatic activity of adenosine triphosphate-competitive kinase inhibitors in BRAF mutant thyroid carcinoma cells

Paolo Salerno, Valentina De Falco, Anna Tamburrino, Tito Claudio Nappi, Giancarlo Vecchio, Rebecca E. Schweppe, Gideon Bollag, Massimo Santoro, Giuliana Salvatore

Research output: Contribution to journalArticle

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Abstract

Context: The V600E mutation accounts for the vast majority of thyroid carcinoma-associated BRAF mutations. Objective: The aim was to study the effects of the two BRAF V600E ATP-competitive kinase inhibitors, PLX4032 and PLX4720, in thyroid carcinoma cell lines. Experimental Design:Weexaminedtheactivity ofPLX4032andPLX4720in thyroidcarcinomacell lines harboring BRAF V600E (8505C, BCPAP, SW1736, BHT101), NRAS Q61R (HTH7), KRAS G12R (CAL62), HRAS G13R (C643), or RET/PTC1 (TPC-1) oncogenes. Normal thyrocytes (PC Cl 3) were used as control. Results: Both compounds inhibited the proliferation of BRAF mutant cell lines, but not normal thyrocytes, with a half maximal effective concentration (EC 50) ranging from 78-113 nM for PLX4720 and from 29-97 nM for PLX4032. Doses equal to or higher than 500 nM were required to achieve a similar effect in BRAF wild-type cancer cells. Phosphorylation of ERK1/2 and MAPK kinase (MEK)1/2 decreased upon PLX4032 and PLX4720 treatment in BRAF mutant thyroid carcinoma cells but not in normal thyroid cells or in cell lines harboring mutations of RAS or RET/PTC1 rearrangements. PLX4032 and PLX4720 treatment induced a G1 block and altered expression of genes involved in the control of G1-S cell-cycle transition. 8505C cell tumor xenografts were smaller in nude mice treated with PLX4032 than in controlmice.This inhibition was associated with reduction of phospho-ERK and phospho-MEK levels. Conclusions: This study provides additional evidence of the promising nature of mutant BRAF as a molecular target for thyroid carcinoma cells.

Original languageEnglish
Pages (from-to)450-455
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume95
Issue number1
DOIs
Publication statusPublished - Jan 2010

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Cytostatic Agents
Thyroid Neoplasms
Phosphotransferases
Adenosine Triphosphate
Cells
Mitogen-Activated Protein Kinase Kinases
Cell Line
Mutation
MAP Kinase Kinase 1
Mitogen-Activated Protein Kinase 3
MAP Kinase Kinase Kinase 1
Oncogenes
Heterografts
Nude Mice
Phosphorylation
Neoplasms
Cell Cycle
Thyroid Gland
Research Design
PLX4032

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Cytostatic activity of adenosine triphosphate-competitive kinase inhibitors in BRAF mutant thyroid carcinoma cells. / Salerno, Paolo; De Falco, Valentina; Tamburrino, Anna; Nappi, Tito Claudio; Vecchio, Giancarlo; Schweppe, Rebecca E.; Bollag, Gideon; Santoro, Massimo; Salvatore, Giuliana.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 95, No. 1, 01.2010, p. 450-455.

Research output: Contribution to journalArticle

Salerno, Paolo ; De Falco, Valentina ; Tamburrino, Anna ; Nappi, Tito Claudio ; Vecchio, Giancarlo ; Schweppe, Rebecca E. ; Bollag, Gideon ; Santoro, Massimo ; Salvatore, Giuliana. / Cytostatic activity of adenosine triphosphate-competitive kinase inhibitors in BRAF mutant thyroid carcinoma cells. In: Journal of Clinical Endocrinology and Metabolism. 2010 ; Vol. 95, No. 1. pp. 450-455.
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abstract = "Context: The V600E mutation accounts for the vast majority of thyroid carcinoma-associated BRAF mutations. Objective: The aim was to study the effects of the two BRAF V600E ATP-competitive kinase inhibitors, PLX4032 and PLX4720, in thyroid carcinoma cell lines. Experimental Design:Weexaminedtheactivity ofPLX4032andPLX4720in thyroidcarcinomacell lines harboring BRAF V600E (8505C, BCPAP, SW1736, BHT101), NRAS Q61R (HTH7), KRAS G12R (CAL62), HRAS G13R (C643), or RET/PTC1 (TPC-1) oncogenes. Normal thyrocytes (PC Cl 3) were used as control. Results: Both compounds inhibited the proliferation of BRAF mutant cell lines, but not normal thyrocytes, with a half maximal effective concentration (EC 50) ranging from 78-113 nM for PLX4720 and from 29-97 nM for PLX4032. Doses equal to or higher than 500 nM were required to achieve a similar effect in BRAF wild-type cancer cells. Phosphorylation of ERK1/2 and MAPK kinase (MEK)1/2 decreased upon PLX4032 and PLX4720 treatment in BRAF mutant thyroid carcinoma cells but not in normal thyroid cells or in cell lines harboring mutations of RAS or RET/PTC1 rearrangements. PLX4032 and PLX4720 treatment induced a G1 block and altered expression of genes involved in the control of G1-S cell-cycle transition. 8505C cell tumor xenografts were smaller in nude mice treated with PLX4032 than in controlmice.This inhibition was associated with reduction of phospho-ERK and phospho-MEK levels. Conclusions: This study provides additional evidence of the promising nature of mutant BRAF as a molecular target for thyroid carcinoma cells.",
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T1 - Cytostatic activity of adenosine triphosphate-competitive kinase inhibitors in BRAF mutant thyroid carcinoma cells

AU - Salerno, Paolo

AU - De Falco, Valentina

AU - Tamburrino, Anna

AU - Nappi, Tito Claudio

AU - Vecchio, Giancarlo

AU - Schweppe, Rebecca E.

AU - Bollag, Gideon

AU - Santoro, Massimo

AU - Salvatore, Giuliana

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N2 - Context: The V600E mutation accounts for the vast majority of thyroid carcinoma-associated BRAF mutations. Objective: The aim was to study the effects of the two BRAF V600E ATP-competitive kinase inhibitors, PLX4032 and PLX4720, in thyroid carcinoma cell lines. Experimental Design:Weexaminedtheactivity ofPLX4032andPLX4720in thyroidcarcinomacell lines harboring BRAF V600E (8505C, BCPAP, SW1736, BHT101), NRAS Q61R (HTH7), KRAS G12R (CAL62), HRAS G13R (C643), or RET/PTC1 (TPC-1) oncogenes. Normal thyrocytes (PC Cl 3) were used as control. Results: Both compounds inhibited the proliferation of BRAF mutant cell lines, but not normal thyrocytes, with a half maximal effective concentration (EC 50) ranging from 78-113 nM for PLX4720 and from 29-97 nM for PLX4032. Doses equal to or higher than 500 nM were required to achieve a similar effect in BRAF wild-type cancer cells. Phosphorylation of ERK1/2 and MAPK kinase (MEK)1/2 decreased upon PLX4032 and PLX4720 treatment in BRAF mutant thyroid carcinoma cells but not in normal thyroid cells or in cell lines harboring mutations of RAS or RET/PTC1 rearrangements. PLX4032 and PLX4720 treatment induced a G1 block and altered expression of genes involved in the control of G1-S cell-cycle transition. 8505C cell tumor xenografts were smaller in nude mice treated with PLX4032 than in controlmice.This inhibition was associated with reduction of phospho-ERK and phospho-MEK levels. Conclusions: This study provides additional evidence of the promising nature of mutant BRAF as a molecular target for thyroid carcinoma cells.

AB - Context: The V600E mutation accounts for the vast majority of thyroid carcinoma-associated BRAF mutations. Objective: The aim was to study the effects of the two BRAF V600E ATP-competitive kinase inhibitors, PLX4032 and PLX4720, in thyroid carcinoma cell lines. Experimental Design:Weexaminedtheactivity ofPLX4032andPLX4720in thyroidcarcinomacell lines harboring BRAF V600E (8505C, BCPAP, SW1736, BHT101), NRAS Q61R (HTH7), KRAS G12R (CAL62), HRAS G13R (C643), or RET/PTC1 (TPC-1) oncogenes. Normal thyrocytes (PC Cl 3) were used as control. Results: Both compounds inhibited the proliferation of BRAF mutant cell lines, but not normal thyrocytes, with a half maximal effective concentration (EC 50) ranging from 78-113 nM for PLX4720 and from 29-97 nM for PLX4032. Doses equal to or higher than 500 nM were required to achieve a similar effect in BRAF wild-type cancer cells. Phosphorylation of ERK1/2 and MAPK kinase (MEK)1/2 decreased upon PLX4032 and PLX4720 treatment in BRAF mutant thyroid carcinoma cells but not in normal thyroid cells or in cell lines harboring mutations of RAS or RET/PTC1 rearrangements. PLX4032 and PLX4720 treatment induced a G1 block and altered expression of genes involved in the control of G1-S cell-cycle transition. 8505C cell tumor xenografts were smaller in nude mice treated with PLX4032 than in controlmice.This inhibition was associated with reduction of phospho-ERK and phospho-MEK levels. Conclusions: This study provides additional evidence of the promising nature of mutant BRAF as a molecular target for thyroid carcinoma cells.

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