Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells

Matti L. Gild, Iñigo Landa, Mabel Ryder, Ronald A. Ghossein, Jeffrey A. Knauf, James A. Fagin

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Inhibitors of RET, a tyrosine kinase receptor encoded by a gene that is frequently mutated in medullary thyroid cancer, have emerged as promising novel therapies for the disease. Rapalogs and other mammalian target of rapamycin (mTOR) inhibitors are effective agents in patients with gastroenteropancreatic neuroendocrine tumors, which share lineage properties with medullary thyroid carcinomas. The objective of this study was to investigate the contribution of mTOR activity to RET-induced signaling and cell growth and to establish whether growth suppression is enhanced by co-targeting RET and mTOR kinase activities. Treatment of the RET mutant cell lines TT, TPC-1, and MZ-CRC-1 with AST487, a RET kinase inhibitor, suppressed growth and showed profound and sustained inhibition of mTOR signaling, which was recapitulated by siRNA-mediated RET knockdown. Inhibition of mTOR with INK128, a dual mTORC1 and mTORC2 kinase inhibitor, also resulted in marked growth suppression to levels similar to those seen with RET blockade. Moreover, combined treatment with AST487 and INK128 at low concentrations suppressed growth and induced apoptosis. These data establish mTOR as a key mediator of RET-mediated cell growth in thyroid cancer cells and provide a rationale for combinatorial treatments in thyroid cancers with oncogenic RET mutations.

Original languageEnglish (US)
Pages (from-to)659-667
Number of pages9
JournalEndocrine-Related Cancer
Volume20
Issue number5
DOIs
StatePublished - Oct 2013

Keywords

  • Drug combinations
  • MTOR
  • MTOR inhibitors
  • Medullary thyroid carcinoma
  • Oncogenic RET
  • RET inhibitors

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Cancer Research

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    Gild, M. L., Landa, I., Ryder, M., Ghossein, R. A., Knauf, J. A., & Fagin, J. A. (2013). Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells. Endocrine-Related Cancer, 20(5), 659-667. https://doi.org/10.1530/ERC-13-0085