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

• DOI: 10.1016/j.xcrm.2024.101868
• Publication Date: 2024-12-09T15:54:23Z
• Authors: Ilya S. Senatorov; Joel Bowman; Keith H. Jansson; Aian Neil Alilin; Brian J. Capaldo; Ross Lake; Morgan Riba; Yasmine C. Abbey; Crystal Mcknight; Xiaohu Zhang; Sonam Raj; Michael L. Beshiri; Paul Shinn; Holly Nguyen; Craig J. Thomas; Eva Corey; Kathleen Kelly
• Keywords: Taxane

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.