Castrate-resistant prostate cancer response to taxane is determined by an HNF1-dependent apoptosis resistance circuit

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. [Display omitted] •Docetaxel elicits the most variable responses in an extensive drug screen of CRPC organoids•A docetaxel response signature identifies an HNF1A-driven drug-resistant phenotype•HNF1A expression in prostate cancer leads to a docetaxel-resistant phenotype•BIRC3 is identified as an actionable target for treating docetaxel-resistant mCRPC Senatorov et al. perform an extensive drug screen using 30 prostate cancer organoid models. A comparison of docetaxel-sensitive and resistant models identifies an HNF1A-driven resistant phenotype. BIRC3 encodes a preserved actionable target in HNF1A+ models, which provides an opportunity for pharmacotherapy via cIAP2 inhibition.