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- W2956145613 abstract "Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that hijack endogenous E3 ubiquitin ligases to induce ubiquitination and subsequent degradation of protein of interest. Recently, it has been shown that PROTACs with robust in vitro and in vivo activities and, in some cases, drug-like pharmaceutical properties can be generated using small molecule ligands for the E3 ligases VHL and CRBN. These findings stoked tremendous enthusiasm on using PROTACs for therapeutics development. Innate and acquired drug resistance often underlies therapeutic failures, particularly for cancer therapy. With the PROTAC technology progressing rapidly towards therapeutic applications, it would be important to understand whether and how resistance to these novel agents may emerge. Using BET-PROTACs as a model system, we demonstrate that resistance to both VHL- and CRBN-based PROTACs can occur in cancer cells following chronic treatment. However, unlike what was often observed for many targeted therapeutics, resistance to BET-PROTACs did not result from secondary mutations that affect compound binding to the target. In contrast, acquired resistance to both VHL- and CRBN-based BET-PROTACs was primarily caused by genomic alterations that compromise core components of the relevant E3 ligase complexes. Citation Format: Bridget Riley-Gillis, Lu Zhang, Priyanka Vijay, Yu Shen. Acquired resistance to BET-PROTACs caused by genomic alterations in core components of E3 ligase complexes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4749." @default.
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- W2956145613 date "2019-07-01" @default.
- W2956145613 modified "2023-09-26" @default.
- W2956145613 title "Abstract 4749: Acquired resistance to BET-PROTACs caused by genomic alterations in core components of E3 ligase complexes" @default.
- W2956145613 doi "https://doi.org/10.1158/1538-7445.am2019-4749" @default.
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