Anti-tumor effects of an ID antagonist with no observed acquired resistance

Abstract ID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocu...

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Autores principales:	Paulina M. Wojnarowicz, Marta Garcia Escolano, Yun-Han Huang, Bina Desai, Yvette Chin, Riddhi Shah, Sijia Xu, Saurabh Yadav, Sergey Yaklichkin, Ouathek Ouerfelli, Rajesh Kumar Soni, John Philip, David C. Montrose, John H. Healey, Vinagolu K. Rajasekhar, William A. Garland, Jeremy Ratiu, Yuan Zhuang, Larry Norton, Neal Rosen, Ronald C. Hendrickson, Xi Kathy Zhou, Antonio Iavarone, Joan Massague, Andrew J. Dannenberg, Anna Lasorella, Robert Benezra
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/fcc94ce778e043e9991e8da7d30777e4
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spelling	oai:doaj.org-article:fcc94ce778e043e9991e8da7d30777e42021-12-02T16:53:05ZAnti-tumor effects of an ID antagonist with no observed acquired resistance10.1038/s41523-021-00266-02374-4677https://doaj.org/article/fcc94ce778e043e9991e8da7d30777e42021-05-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00266-0https://doaj.org/toc/2374-4677Abstract ID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impairs cell growth and viability that results from an increase in reactive oxygen species (ROS) production upon ID degradation. In mouse models, AGX51 treatment suppresses breast cancer colonization in the lung, regresses the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduces tumor burden in sporadic colorectal neoplasia. Furthermore, in cells and mice, we fail to observe acquired resistance to AGX51 likely the result of the inability to mutate the binding pocket without loss of ID function and efficient degradation of the ID proteins. Thus, AGX51 is a first-in-class compound that antagonizes ID proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.Paulina M. WojnarowiczMarta Garcia EscolanoYun-Han HuangBina DesaiYvette ChinRiddhi ShahSijia XuSaurabh YadavSergey YaklichkinOuathek OuerfelliRajesh Kumar SoniJohn PhilipDavid C. MontroseJohn H. HealeyVinagolu K. RajasekharWilliam A. GarlandJeremy RatiuYuan ZhuangLarry NortonNeal RosenRonald C. HendricksonXi Kathy ZhouAntonio IavaroneJoan MassagueAndrew J. DannenbergAnna LasorellaRobert BenezraNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Paulina M. Wojnarowicz Marta Garcia Escolano Yun-Han Huang Bina Desai Yvette Chin Riddhi Shah Sijia Xu Saurabh Yadav Sergey Yaklichkin Ouathek Ouerfelli Rajesh Kumar Soni John Philip David C. Montrose John H. Healey Vinagolu K. Rajasekhar William A. Garland Jeremy Ratiu Yuan Zhuang Larry Norton Neal Rosen Ronald C. Hendrickson Xi Kathy Zhou Antonio Iavarone Joan Massague Andrew J. Dannenberg Anna Lasorella Robert Benezra Anti-tumor effects of an ID antagonist with no observed acquired resistance
description	Abstract ID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impairs cell growth and viability that results from an increase in reactive oxygen species (ROS) production upon ID degradation. In mouse models, AGX51 treatment suppresses breast cancer colonization in the lung, regresses the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduces tumor burden in sporadic colorectal neoplasia. Furthermore, in cells and mice, we fail to observe acquired resistance to AGX51 likely the result of the inability to mutate the binding pocket without loss of ID function and efficient degradation of the ID proteins. Thus, AGX51 is a first-in-class compound that antagonizes ID proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.
format	article
author	Paulina M. Wojnarowicz Marta Garcia Escolano Yun-Han Huang Bina Desai Yvette Chin Riddhi Shah Sijia Xu Saurabh Yadav Sergey Yaklichkin Ouathek Ouerfelli Rajesh Kumar Soni John Philip David C. Montrose John H. Healey Vinagolu K. Rajasekhar William A. Garland Jeremy Ratiu Yuan Zhuang Larry Norton Neal Rosen Ronald C. Hendrickson Xi Kathy Zhou Antonio Iavarone Joan Massague Andrew J. Dannenberg Anna Lasorella Robert Benezra
author_facet	Paulina M. Wojnarowicz Marta Garcia Escolano Yun-Han Huang Bina Desai Yvette Chin Riddhi Shah Sijia Xu Saurabh Yadav Sergey Yaklichkin Ouathek Ouerfelli Rajesh Kumar Soni John Philip David C. Montrose John H. Healey Vinagolu K. Rajasekhar William A. Garland Jeremy Ratiu Yuan Zhuang Larry Norton Neal Rosen Ronald C. Hendrickson Xi Kathy Zhou Antonio Iavarone Joan Massague Andrew J. Dannenberg Anna Lasorella Robert Benezra
author_sort	Paulina M. Wojnarowicz
title	Anti-tumor effects of an ID antagonist with no observed acquired resistance
title_short	Anti-tumor effects of an ID antagonist with no observed acquired resistance
title_full	Anti-tumor effects of an ID antagonist with no observed acquired resistance
title_fullStr	Anti-tumor effects of an ID antagonist with no observed acquired resistance
title_full_unstemmed	Anti-tumor effects of an ID antagonist with no observed acquired resistance
title_sort	anti-tumor effects of an id antagonist with no observed acquired resistance
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/fcc94ce778e043e9991e8da7d30777e4
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Anti-tumor effects of an ID antagonist with no observed acquired resistance

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