Development of an orally bioavailable SWI/SNF ATPase degrader and acquired mechanisms of resistance [RNA-seq]
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. Overall design: All the AURs cell line were treated in vitro with SMARCA2/4 degrader (AU-15330, abbreviated as AU) and accquired resistance to AU.