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Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells

Matti L Gild1, Iñigo Landa, Mabel Ryder

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

Endocrine-Related Cancer
|July 6, 2013
PubMed

Insights

Targeting the mammalian target of rapamycin (mTOR) pathway alongside RET kinase may enhance treatments for medullary thyroid cancer. Inhibiting both RET and mTOR significantly suppressed cancer cell growth and induced apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • RET kinase mutations are common in medullary thyroid cancer (MTC).
  • Mammalian target of rapamycin (mTOR) inhibitors show efficacy in related neuroendocrine tumors.
  • The role of mTOR in RET-driven MTC signaling is not fully understood.

Purpose of the Study:

  • Investigate mTOR's contribution to RET-induced signaling and MTC cell growth.
  • Determine if co-targeting RET and mTOR enhances growth suppression.

Main Methods:

  • Utilized RET mutant MTC cell lines (TT, TPC-1, MZ-CRC-1).
  • Treated cells with AST487 (RET inhibitor) and INK128 (mTOR inhibitor).
  • Employed siRNA for RET knockdown to confirm findings.

Main Results:

  • RET inhibition by AST487 suppressed MTC cell growth and mTOR signaling.
  • siRNA-mediated RET knockdown mimicked AST487 effects.
  • mTOR inhibition with INK128 also significantly reduced cell growth.
  • Combined RET and mTOR inhibition induced apoptosis and enhanced growth suppression.

Conclusions:

  • mTOR is a critical mediator of RET-driven growth in MTC cells.
  • Co-targeting RET and mTOR presents a promising therapeutic strategy for MTC.
  • This study provides a rationale for combinatorial therapies in RET-mutated thyroid cancers.
Keywords:
RET inhibitorsdrug combinationsmTORmTOR inhibitorsmedullary thyroid carcinomaoncogenic RET

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