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Development of an orally bioavailable SWI/SNF ATPase degrader and acquired mechanisms of resistance [RNA-seq]

GSE250326 Homo sapiens Expression profiling by high throughput sequencing 8 samples Submitted 2024/03/15 Platform GPL24676
Summary
SWI/SNF ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here we developed AU-24118, a first-in-class, orally bioavailable degrader of SMARCA2/4 and PBRM1. AU-24118 demonstrated tumor regression in a castration resistant model of prostate cancer which was further enhanced in combination with enzalutamide. Prostate cancer cell lines exposed to increasing doses of a SWI/SNF degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. While SMARCA4 mutations provided specific resistance to SWI/SNF degraders, ABCB1 overexpression provided broader resistance to other compounds as well as could be overcome with ABCB1 inhibition.
Published in
Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer
He T, Cheng C, Qiao Y et al. · bioRxiv : the preprint server for biology 2024 · PMID 38464081 · doi:10.1101/2024.02.29.582768
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Also filed as BioProject PRJNA1053372 and SRA study SRP478286. Searching any of these in the dataset finder brings you back here.

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