TY - JOUR
T1 - YM155 Induces DNA Damage and Cell Death in Anaplastic Thyroid Cancer Cells by Inhibiting DNA Topoisomerase IIα at the ATP-Binding Site
AU - Mackay, Ryan P.
AU - Weinberger, Paul M.
AU - Copland, John A.
AU - Mahdavian, Elahe
AU - Xu, Qinqin
N1 - Funding Information:
We would like to thank Dr. S. Ohata for cell line ACT1 and Dr. Copland for ATC cell lines THJ11T, THJ16T, and THJ29T. This work was supported by funding from NIH F30 GM142199-01 (to R.P. Mackay). This work was also supported in part by Louisiana State University Health Sciences Center – Shreveport Weinberger Lab Startup funding and Cherie-Ann Nathan Distinguished Professor of Otolaryngology/ Head & Neck Surgery Endowed Professorship (to P.M. Weinberger). The majority of this work was performed at Louisiana State University Health Sciences Center – Shreveport, Shreveport, LA. The collection of thyroid cancer patient tissue samples and gene chip analysis was performed at Mayo Clinic, Jacksonville, FL, and only deidentified data were shared with the current study team. Molecular modeling was performed at Louisiana State University in Shreveport, Shreveport, LA.
Funding Information:
We would like to thank Dr. S. Ohata for cell line ACT1 and Dr. Copland for ATC cell lines THJ11T, THJ16T, and THJ29T. This work was supported by funding from NIH F30 GM142199-01 (to R.P. Mackay). This work was also supported in part by Louisiana State University Health Sciences Center – Shreveport Weinberger Lab Startup funding and Cherie-Ann Nathan Distinguished Professor of Otolaryngology/ Head & Neck Surgery Endowed Professorship (to P.M. Weinberger).
Publisher Copyright:
©2022 American Association for Cancer Research
PY - 2022/6
Y1 - 2022/6
N2 - Anaplastic thyroid cancer (ATC) is among the most aggressive erase Top2a compared with benign thyroid samples and to of human cancers, and currently there are few effective treatments differentiated thyroid cancers. ATC cell lines that overexpress for most patients. YM155, first identified as a survivin inhibitor, Top2a are more sensitive to YM155. We created a YM155-was highlighted in a high-throughput screen performed by the resistant cell line, which shows decreased expression of Top2a National Cancer Institute, killing ATC cells in vitro and in vivo. and is resensitized with Top2a overexpression. Molecular model-However, there was no association between survivin expression ing predicts binding for YM155 in the Top2a ATP-binding site and response to YM155 in clinical trials, and YM155 has been and identifies key amino acids for YM155–Top2a interaction. A mostly abandoned for development despite favorable pharmacoTop2a mutant abrogates the effect of YM155, confirming the kinetic and toxicity profiles. Currently, alternative mechanisms contribution of Top2a to YM155 mechanism of action. Our are being explored for YM155 by a number of groups. In this results suggest a novel mechanism of action for YM155 and may study, ATC patient samples show overexpression of topoisomrepresent a new therapeutic approach for the treatment of ATC.
AB - Anaplastic thyroid cancer (ATC) is among the most aggressive erase Top2a compared with benign thyroid samples and to of human cancers, and currently there are few effective treatments differentiated thyroid cancers. ATC cell lines that overexpress for most patients. YM155, first identified as a survivin inhibitor, Top2a are more sensitive to YM155. We created a YM155-was highlighted in a high-throughput screen performed by the resistant cell line, which shows decreased expression of Top2a National Cancer Institute, killing ATC cells in vitro and in vivo. and is resensitized with Top2a overexpression. Molecular model-However, there was no association between survivin expression ing predicts binding for YM155 in the Top2a ATP-binding site and response to YM155 in clinical trials, and YM155 has been and identifies key amino acids for YM155–Top2a interaction. A mostly abandoned for development despite favorable pharmacoTop2a mutant abrogates the effect of YM155, confirming the kinetic and toxicity profiles. Currently, alternative mechanisms contribution of Top2a to YM155 mechanism of action. Our are being explored for YM155 by a number of groups. In this results suggest a novel mechanism of action for YM155 and may study, ATC patient samples show overexpression of topoisomrepresent a new therapeutic approach for the treatment of ATC.
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U2 - 10.1158/1535-7163.MCT-21-0619
DO - 10.1158/1535-7163.MCT-21-0619
M3 - Article
C2 - 35405742
AN - SCOPUS:85131218221
SN - 1535-7163
VL - 21
SP - 925
EP - 935
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 6
ER -