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

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

doi:10.18632/oncotarget.3833

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.

Highlights

Anaplastic thyroid cancer (ATC) is one of the most deadly solid human malignancies
In addition to inhibiting mTOR and the downstream effectors of the mTOR pathway (4E-BP1 and S6K), Torin2 inhibited the phosphorylation of AKT, an important signaling (PI3K/ AKT/mTOR)-pathway in ATC and a variety of cancers [24]
We show Torin2 to be more active than current therapies such as docetaxel and doxorubicin, and demonstrate that the targets of Torin2 are upregulated in ATC making it an attractive targeted therapy for ATC

Summary

Introduction

Anaplastic thyroid cancer (ATC) is one of the most deadly solid human malignancies. It represents less than 2% of all thyroid cancers, has an annual incidence of 1-2 cases per million population per year but accounts for nearly one-third of thyroid cancer deaths [1, 2]. The median survival of patients with ATC is less than 6 month, and 90% of patients with ATC present with unresectable locally advanced or distant metastatic disease at time of diagnosis [3, 4]. There is an unmet need to identify effective agents for the treatment of ATC. Drug discovery and development can be costly and take a long time to identify a clinically effective agent

Methods

Results

Conclusion