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Development and Application of Rapamycin-regulated Tyrosine Phosphatases
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Mammalian target of rapamycin pathway activation is associated to RET mutation status in medullary thyroid carcinoma

Ida Rapa1, Enrico Saggiorato, Daniela Giachino

  • 1Department of Clinical and Biological Sciences, University of Turin, San Luigi Hospital, 10043 Orbassano, Turin, Italy.

The Journal of Clinical Endocrinology and Metabolism
|May 6, 2011
PubMed
Abstract

Insights

Medullary thyroid carcinoma (MTC) genetic pathways are largely unknown. This study found the mTOR pathway activated in MTC, particularly with germline RET mutations, while downstream genes like BRAF and RAS were not mutated.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Genetic mutations driving medullary thyroid carcinomas (MTC) remain largely uncharacterized, with the exception of RET mutations.
  • Understanding downstream protein activation following RET tyrosine kinase phosphorylation is crucial for MTC research.

Purpose of the Study:

  • To identify mutations in genes downstream of RET activation in MTC.
  • To map the activation patterns of intracellular regulators controlling cell growth.

Main Methods:

  • Analysis of 49 MTC cases for mutations in RET, BRAF, RAS isoforms, and PI3 kinase genes.
  • Immunohistochemical analysis of intracellular transducers.
  • In vitro assessment of mammalian target of rapamycin (mTOR) inhibition on TT cells.

Main Results:

  • No mutations were found in BRAF, RAS isoforms, or PI3 kinase.
  • RET mutations were present in 20% of germline cases and 53% of sporadic tumors.
  • Phospho-mTOR, phospho-AKT, and phospho-p70S6K expression correlated with germline RET mutations, and mTOR inhibition impacted RET-mutant cell proliferation.

Conclusions:

  • The mTOR intracellular signaling pathway is activated in MTC, especially in cases with germline RET mutations.
  • Genes downstream of RET tyrosine kinase, including BRAF, RAS, and PI3 kinase, are not mutated in MTC.

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