Inhibition of survivin with YM155 induces durable tumor response in anaplastic thyroid cancer

Amit Mehta, Lisa Zhang, Myriem Boufraqech, Yi Liu-Chittenden, Yaqin Zhang, Dhaval Patel, Sean Davis, Avi Rosenberg, Kris Ylaya, Rachel Aufforth, Zhuyin Li, Min Shen, Electron Kebebew

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy without any effective therapy. The aim of this study is to use a high-throughput drug library screening to identify a novel therapeutic agent that targets dysregulated genes/pathways in ATC. Experimental Design: We performed quantitative highthroughput screening (qHTS) in ATC cell lines using a compound library of 3,282 drugs. Dysregulated genes in ATC were analyzed using genome-wide expression analysis and immunohistochemistry in human ATC tissue samples and ATC cell lines. In vitro and in vivo studies were performed for determining drug activity, effectiveness of targeting, and the mechanism of action. Results: qHTS identified 100 active compounds in three ATC cell lines. One of the most active agents was the first-in-class survivin inhibitor YM155. Genome-wide expression analysis and immunohistochemistry showed overexpression of survivin in human ATC tissue samples, and survivin was highly expressed in all ATC cell lines tested. YM155 significantly inhibited ATC cellular proliferation. Mechanistically, YM155 inhibited survivin expression in ATC cells. Furthermore, YM155 treatment reduced claspin expression, which was associated with S-phase arrest in ATC cells. In vivo, YM155 significantly inhibited growth and metastases and prolonged survival. Conclusions: Our data show that YM155 is a promising anticancer agent for ATC and that its target, survivin, is overexpressed in ATC. Our findings support the use of YM155 in clinical trials as a therapeutic option in advanced and metastatic ATC.

Original languageEnglish (US)
Pages (from-to)4123-4132
Number of pages10
JournalClinical Cancer Research
Volume21
Issue number18
DOIs
StatePublished - Sep 15 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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