Wojnarowicz, Paulina M, Escolano, Marta Garcia, Huang, Yun-Han, Desai, Bina, Chin, Yvette, Shah, Riddhi, Xu, Sijia, Yadav, Saurabh, Yaklichkin, Sergey, Ouerfelli, Ouathek, Soni, Rajesh Kumar, Philip, John, Montrose, David C, Healey, John H, Rajasekhar, Vinagolu K, Garland, William A, Ratiu, Jeremy, Zhuang, Yuan, Norton, Larry, Rosen, Neal, Hendrickson, Ronald C, Zhou, Xi Kathy, Iavarone, Antonio, Massague, Joan, Dannenberg, Andrew J, Lasorella, Anna, Benezra, Robert (May 2021) Anti-tumor effects of an ID antagonist with no observed acquired resistance. npj Breast Cancer, 7 (1). p. 58. ISSN 2374-4677
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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > cancer > cancer types > breast cancer diseases & disorders > cancer > drugs and therapies |
| CSHL Authors: | |
| Communities: | CSHL labs > Wigler lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 24 May 2021 |
| Date Deposited: | 01 Jun 2021 19:22 |
| Last Modified: | 15 Nov 2023 18:44 |
| PMCID: | PMC8144414 |
| URI: | https://repository.cshl.edu/id/eprint/40178 |
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