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YM155 Induces DNA Damage and Cell Death in Anaplastic Thyroid Cancer Cells by Inhibiting DNA Topoisomerase IIα at the

Ryan P Mackay1,2, Paul M Weinberger1,2, John A Copland3

  • 1Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health Sciences Center - Shreveport, Shreveport, Louisiana.

Molecular Cancer Therapeutics
|April 11, 2022
PubMed

Insights

YM155 shows promise in treating anaplastic thyroid cancer (ATC) by targeting topoisomerase Top2α, not survivin. This discovery offers a new therapeutic strategy for aggressive thyroid cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Anaplastic thyroid cancer (ATC) is highly aggressive with limited treatment options.
  • YM155, a potential survivin inhibitor, showed efficacy against ATC but lacked correlation with survivin levels in trials.
  • Previous development of YM155 stalled due to unclear mechanisms, despite favorable drug properties.

Purpose of the Study:

  • To investigate alternative mechanisms of action for YM155 in anaplastic thyroid cancer.
  • To explore the role of topoisomerase Top2α in YM155 sensitivity and efficacy.
  • To identify a novel therapeutic target for YM155 in ATC treatment.

Main Methods:

  • Compared topoisomerase Top2α expression in ATC, benign thyroid, and differentiated thyroid cancer samples.
  • Assessed YM155 sensitivity in ATC cell lines with varying Top2α expression levels.
  • Utilized molecular modeling to predict YM155 binding to Top2α and created a Top2α mutant to confirm interaction.

Main Results:

  • Anaplastic thyroid cancer samples exhibited higher Top2α expression than benign or differentiated thyroid tissues.
  • ATC cell lines overexpressing Top2α demonstrated increased sensitivity to YM155.
  • A YM155-resistant cell line showed reduced Top2α levels, which were restored upon Top2α re-expression, re-sensitizing the cells.
  • Molecular modeling and mutant analysis confirmed YM155 binds to the Top2α ATP-binding site, mediating its effect.

Conclusions:

  • Topoisomerase Top2α is a key mediator of YM155's anti-cancer activity in anaplastic thyroid cancer.
  • YM155's efficacy is linked to Top2α expression, suggesting it as a predictive biomarker.
  • This research identifies a novel mechanism for YM155 and presents a potential new therapeutic strategy for ATC.

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