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Torin2 targets dysregulated pathways in anaplastic thyroid cancer and inhibits tumor growth and metastasis

Samira M Sadowski1, Myriem Boufraqech1, Lisa Zhang1

  • 1Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Oncotarget
|May 7, 2015
PubMed

Insights

Anaplastic thyroid cancer (ATC) lacks effective therapies. Researchers screened drugs and found Torin2, targeting the mTOR pathway, effectively inhibited ATC cell growth, migration, and metastasis in preclinical models, offering a promising new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Anaplastic thyroid cancer (ATC) is a rare and highly lethal malignancy with limited therapeutic options.
  • There is an urgent need for novel therapeutic agents to treat ATC.

Purpose of the Study:

  • To identify potential therapeutic agents for ATC through quantitative high-throughput screening (qHTS).
  • To investigate the efficacy of Torin2, an mTOR inhibitor, in preclinical models of ATC.

Main Methods:

  • Quantitative high-throughput screening (qHTS) of 3,282 drugs in ATC cell lines.
  • In vitro studies assessing Torin2's effects on cell proliferation, apoptosis, cell cycle, and migration.
  • In vivo studies using a metastatic ATC mouse model to evaluate Torin2's efficacy on tumor growth and survival.

Main Results:

  • qHTS identified 100 pan-active agents, with mTOR inhibitors showing high efficacy, particularly Torin2.
  • Torin2 demonstrated dose-dependent inhibition of ATC cell proliferation, induced apoptosis, caused G1/S phase arrest, and inhibited migration.
  • Torin2 suppressed mTOR pathway signaling, reduced claspin and survivin expression, inhibited tumor growth and metastasis, and prolonged survival in a mouse model.

Conclusions:

  • Torin2 effectively targets the upregulated mTOR pathway in ATC.
  • Torin2 shows significant promise as a therapeutic agent for anaplastic thyroid cancer.
Keywords:
Torin2anaplastic thyroid cancermTORmTORC1 inhibitorquantitative high-troughput screening

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