In vitro transforming potential, intracellular signaling properties, and sensitivity to a kinase inhibitor (sorafenib) of RET proto-oncogene variants Glu511Lys, Ser649Leu, and Arg886Trp

• Type: Article in International Scientific Journal
• Date: 2011

Authors

Hugo Prazeres (Author) Other; Joana P Couto (Author) Other; Fernando Rodrigues (Author) Other; Joao Vinagre (Author) Other; Joana Torres (Author) Other; Vitor Trovisco (Author) Other; Teresa C Martins (Author) Other; Manuel Sobrinho Simoes (Author) FMUP; Paula Soares (Author) FMUP

Journal

Title: Endocrine-Related Cancer

Vol. 18 No. 4

Pages: 401-412

ISSN: 1351-0088

Publisher: BioScientifica Ltd.

Indexing

ISI Web of Knowledge - 11 Citations

Scopus - 10 Citations

Pubmed / Medline

Scientific classification

FOS: Medical and Health sciences > Clinical medicine

CORDIS: Health sciences

Other information

Authenticus ID: P-002-NY0

DOI: 10.1530/erc-10-0258

Resumo (PT): Endocr Relat Cancer

Abstract (EN): Multiple endocrine neoplasia type 2 and a subset of apparently sporadic medullary thyroid carcinoma (AS-MTC) are caused by germ line activating point mutations of the rearranged during transfection (RET) proto-oncogene. RET encodes a receptor with tyrosine kinase activity that targets several intracellular signaling cascades, such as RAS-RAF-ERK1/2, PIK3-AKT, and STAT transcription factors. The objective of this study was to assess the function of three germ line RET variants Arg886Trp, Ser649Leu, and Glu511Lys of undetermined pathogenic significance, which were found in three kindreds of isolated AS-MTC. For this purpose, we employed vectors expressing each of the RET variants and measured the number of NIH3T3 transformation foci and soft agar colonies, the degree of activation of known RET intracellular signaling targets (ERK1/2, STAT1, STAT3, and TCF4), and the extent of ERK1/2 inhibition on sorafenib treatment. We found that RET variants Arg886Trp and Glu511Lys have shown increased in vitro transforming potential in a glial-derived neurotrophic factor-dependent manner. In contrast, the Ser649Leu variant did not significantly increased the number of foci and agar colonies relative to wild-type RET (RET-WT). The variants Glu511Lys and Arg886Trp showed 10- and 12.5-fold ERK1/2 activation respectively, that was significantly higher than that observed for RET-WT (fivefold). Increased levels of STAT1 and TCF4 activation were only observed for RET Arg886Trp (2.5- and 3-fold versus 1.2- and 2-fold in RET-WT respectively). The three RET variants analyzed here were sensitive to treatment with sorafenib. In conclusion, our results allow to classify previously uncharacterized RET genotypes, which may be of use to define follow-up and therapeutic regimens. Endocrine-Related Cancer (2011) 18 401-412

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12