Castrate Resistant Prostate Cancer Response to Taxane is Determined by an HNF1-dependent Apoptosis Resistance Circuit (RNA-Seq)

Metastatic castrate-resistant prostate cancer (mCRPC) is a genetically and phenotypically heterogeneous cancer where advancements are needed in biomarker discovery and targeted therapy. A critical and often effective component of treatment includes taxanes. We performed one of the first high throughput screens across a cohort of 30 diverse patient-derived CRPC organoids to a library of 78 drugs. Combining quantitative response measures with transcriptomic analyses demonstrated that HNF1 Homeobox A (HNF1A) drives a transcriptional program of taxane resistance, dependent upon cellular inhibitor of apoptosis protein 2 (cIAP2). Monotherapy with cIAP2 inhibitor LCL161 was sufficient to treat HNF1A+ models of mCRPC previously resistant to docetaxel. RNA-seq for LuCaP 23.1 organoids with and without HNF1A expression *************************************************************** Submitter states that missing raw data are being made available for controlled access in dbGaP under accession ID: phs001587.v3.p1 ***************************************************************