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Anti-tumor effects of an Id antagonist with no acquired resistance

Paulina M. Wojnarowicz, Marta Garcia Escolano, Yun-Han Huang, Bina Desai, Yvette Chin, Riddhi Shah, Sijia Xu, Ouathek Ouerfelli, Rajesh Kumar Soni, John Philip, David C. Montrose, John H. Healey, Vinagolu K. Rajasekhar, William A. Garland, Larry Norton, Neal Rosen, Ronald C. Hendrickson, Xi Kathy Zhou, Antonio Iavarone, Joan Massague, Andrew J. Dannenberg, Anna Lasorella, Robert Benezra
doi: https://doi.org/10.1101/2020.01.06.894840
Paulina M. Wojnarowicz
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY
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Marta Garcia Escolano
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY
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Yun-Han Huang
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY
2Weill Cornell/Sloan Kettering/Rockefeller Tri-Institutional MD-PhD Program, New York, NY 10065
3Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, NY 10065
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Bina Desai
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY
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Yvette Chin
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY
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Riddhi Shah
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY
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Sijia Xu
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY
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Ouathek Ouerfelli
4Organic Synthesis Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY
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Rajesh Kumar Soni
5Proteomics & Microchemistry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY
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John Philip
5Proteomics & Microchemistry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY
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David C. Montrose
6Department of Medicine, Weill Cornell Medical College, New York, NY
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John H. Healey
7Orthopedics Service, Memorial Sloan Kettering Cancer Center, New York, NY
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Vinagolu K. Rajasekhar
8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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William A. Garland
9Tosk, Inc., Mountain View, CA
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Larry Norton
10Evelyn H. Lauder Breast Center, Memorial Sloan Kettering Cancer Center, New York, NY
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Neal Rosen
11Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY
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Ronald C. Hendrickson
5Proteomics & Microchemistry Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY
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Xi Kathy Zhou
12Department of Healthcare Policy and Research Weill Cornell Medical College, New York, NY
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Antonio Iavarone
13Department of Neurology, Department of Pathology, Institute for Cancer Genetics, Columbia University Medical Center, New York, NY
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Joan Massague
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY
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Andrew J. Dannenberg
6Department of Medicine, Weill Cornell Medical College, New York, NY
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Anna Lasorella
14Department of Pediatrics, Department of Pathology, Institute for Cancer Genetics, Columbia University Medical Center, New York, NY
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Robert Benezra
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY
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  • For correspondence: benezrar@mskcc.org
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Summary

Id proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. Id proteins inhibit basic HLH transcription factors through protein-protein interactions, often inhibiting differentiation and sustaining proliferation. We recently identified a small-molecule, AGX51, which targets Id proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impaired cell growth and viability that results from a dramatic increase in ROS production upon Id degradation. In mouse models, AGX51 treatment suppressed breast cancer colonization in the lung, regressed the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduced tumor burden in a model of sporadic colorectal neoplasia. Furthermore, in cells and mice, we failed to observe acquired resistance to AGX51 likely the result of the immutability of the binding pocket 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.

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Posted January 06, 2020.
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Anti-tumor effects of an Id antagonist with no acquired resistance
Paulina M. Wojnarowicz, Marta Garcia Escolano, Yun-Han Huang, Bina Desai, Yvette Chin, Riddhi Shah, Sijia Xu, Ouathek Ouerfelli, Rajesh Kumar Soni, John Philip, David C. Montrose, John H. Healey, Vinagolu K. Rajasekhar, William A. Garland, Larry Norton, Neal Rosen, Ronald C. Hendrickson, Xi Kathy Zhou, Antonio Iavarone, Joan Massague, Andrew J. Dannenberg, Anna Lasorella, Robert Benezra
bioRxiv 2020.01.06.894840; doi: https://doi.org/10.1101/2020.01.06.894840
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Anti-tumor effects of an Id antagonist with no acquired resistance
Paulina M. Wojnarowicz, Marta Garcia Escolano, Yun-Han Huang, Bina Desai, Yvette Chin, Riddhi Shah, Sijia Xu, Ouathek Ouerfelli, Rajesh Kumar Soni, John Philip, David C. Montrose, John H. Healey, Vinagolu K. Rajasekhar, William A. Garland, Larry Norton, Neal Rosen, Ronald C. Hendrickson, Xi Kathy Zhou, Antonio Iavarone, Joan Massague, Andrew J. Dannenberg, Anna Lasorella, Robert Benezra
bioRxiv 2020.01.06.894840; doi: https://doi.org/10.1101/2020.01.06.894840

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