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This version published online on October 30, 2009
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2009-0373
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Submitted on February 18, 2009
Accepted on September 23, 2009

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*, and Giuliana Salvatore

Dipartimento di Biologia e Patologia Cellulare e Molecolare c/o Istituto di Endocrinologia ed Oncologia Sperimentale Consiglio Nazionale delle Ricerche (P.S., V.D.F., A.T., T.C.N., G.V., M.S.), Universita "Federico II," 80131 Naples, Italy; Division of Endocrinology, Diabetes, and Metabolism (R.E.S.), University of Colorado Denver, Aurora, Colorado 80045; Plexxikon Inc. (G.B.), Berkeley, California 94710; and Dipartimento di Studi delle Istituzioni e dei Sistemi Territoriali (G.S.), Universita "Parthenope," 80133 Naples, Italy

* To whom correspondence should be addressed. E-mail: masantor{at}unina.it.

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: We examined the activity of PLX4032 and PLX4720 in thyroid carcinoma cell 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 (EC50) 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 ERK 1/2 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 control mice. 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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