Abstract
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 perform a high-throughput screen across a cohort of 30 diverse patient-derived castrate-resistant prostate cancer (CRPC) organoids to a library of 78 drugs. Combining quantitative response measures with transcriptomic analyses demonstrates that HNF1 homeobox A (HNF1A) drives a transcriptional program of taxane resistance, commonly dependent upon cellular inhibitor of apoptosis protein 2 (cIAP2). Monotherapy with cIAP2 inhibitor LCL161 is sufficient to treat HNF1A+ models of mCRPC previously resistant to docetaxel. These data may be useful in future clinical trial designs.