Document Detail


Activation of the RAS/RAF/ERK Signaling Pathway Contributes to Resistance to Sunitinib in Thyroid Carcinoma Cell Lines.
MedLine Citation:
PMID:  22442268     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Context:Sunitinib is currently being evaluated in advanced human thyroid carcinomas, based on the rationale that the vascular endothelial growth factor and platelet-derived growth factor receptors and the RET/PTC rearrangement are valuable targets for the treatment of this malignancy. However, criteria for selecting thyroid tumors that may benefit from sunitinib are lacking.Design:The effect of activating somatic mutations in the KRAS and BRAF genes on the responsiveness to sunitinib was evaluated in a panel of thyroid cancer cell lines harboring wild-type KRAS and BRAF genes, the RET/PTC1 rearrangement, the G12R KRAS, or the V600E BRAF mutation.Results:Sunitinib was found to selectively inhibit cell proliferation, induce cell accumulation in the G0-G1 phase, and inhibit the phosphorylation of ERK1/2 in both KRAS/BRAF wild-type thyroid cancer cells and in tumor cells harboring the RET/PTC rearrangement, whereas it was completely ineffective in KRAS- or BRAF-mutated thyroid carcinoma cells. This differential antitumor activity of sunitinib did not correlate with the expression profile of the vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor-α and cKIT genes. Of note, the constitutive activation of RAS/RAF/ERK signaling in KRAS/BRAF wild-type cells by transfection of the R12 HRAS or V600E BRAF mutants or stimulation with epithelial growth factor resulted in the loss of responsiveness to sunitinib, whereas pharmacological inhibition of MAPK kinase activity resulted in the resensitization of KRAS- or BRAF-mutated cells to the multikinase inhibitor.Conclusions:The constitutive activation of the RAS/RAF/ERK pathway may favor resistance to sunitinib in thyroid carcinoma cells.
Authors:
Annamaria Piscazzi; Eleonora Costantino; Francesca Maddalena; Maria Iole Natalicchio; Assunta Maria Teresa Gerardi; Raffaele Antonetti; Mauro Cignarelli; Matteo Landriscina
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-22
Journal Detail:
Title:  The Journal of clinical endocrinology and metabolism     Volume:  -     ISSN:  1945-7197     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-23     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0375362     Medline TA:  J Clin Endocrinol Metab     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Clinical Oncology Unit (A.P., E.C., A.M.T.G., M.L.), Department of Medical Sciences, and Endocrinology Unit (M.C.), Department of Medical Sciences, University of Foggia, 71122 Foggia, Italy; Laboratory of Pre-clinical and Translational Research, Instituto di Ricovero e Cura a Carattere Scientifico-Centro di Riferimento Oncologico Regionale della Basilicata (F.M.), 85028 Rionero in Vulture, Italy; and Molecular Biology Laboratory (M.I.N., R.A.), Azienda Ospedali Riuniti, Foggia, Italy.
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