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

Samira M. Sadowski, Myriem Boufraqech, Lisa Zhang, Amit Mehta, Payal Kapur, Yaqin Zhang, Zhuyin Li, Min Shen, Electron Kebebew

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Anaplastic thyroid cancer (ATC) is rare but it is one of the most lethal human malignancies with no effective therapy. There is a pressing need to identify new therapeutic agents for ATC. We performed quantitative high-throughput screening (qHTS) in ATC cell lines using a compound library of 3,282 drugs. qHTS identified 100 pan-active agents. Enrichment analysis of qHTS data showed drugs targeting mTOR were one of the most active drug categories, and Torin2 showed the highest efficacy. We found mTOR to be upregulated in ATC. Treatment of multiple ATC cell lines with Torin2 showed significant dose-dependent inhibition of cellular proliferation with caspase-dependent apoptosis and G1/S phase arrest. Torin2 inhibited cellular migration and inhibited the phosphorylation of key effectors of the mTOR-pathway (AKT, 4E-BP1 and 70S6K), as well as claspin and survivin expression, regulators of cell cycle and apoptosis. In our in vivo mouse model of metastatic ATC, Torin2 inhibited tumor growth and metastasis and significantly prolonged overall survival. Our findings suggest that Torin2 is a promising agent for ATC therapy and that it effectively targets upregulated pathways in human ATC.

Original languageEnglish (US)
Pages (from-to)18038-18049
Number of pages12
JournalOncotarget
Volume6
Issue number20
DOIs
StatePublished - 2015

Keywords

  • Anaplastic thyroid cancer
  • Quantitative high-troughput screening
  • Torin2
  • mTOR
  • mTORC1 inhibitor

ASJC Scopus subject areas

  • Oncology

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    Sadowski, S. M., Boufraqech, M., Zhang, L., Mehta, A., Kapur, P., Zhang, Y., Li, Z., Shen, M., & Kebebew, E. (2015). Torin2 targets dysregulated pathways in anaplastic thyroid cancer and inhibits tumor growth and metastasis. Oncotarget, 6(20), 18038-18049. https://doi.org/10.18632/oncotarget.3833