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.
Authors
- Holly M. Nguyen (ORCID: https://orcid.org/0000-0002-6331-8089)
- Craig J. Thomas (ORCID: https://orcid.org/0000-0001-9386-9001)
- Michael L. Beshiri (ORCID: https://orcid.org/0000-0003-3128-3851)
- Eva Corey (ORCID: https://orcid.org/0000-0002-9244-3807)
- Keith H. Jansson
- Morgan Riba
- Ross Lake (ORCID: https://orcid.org/0000-0002-6929-0793)
- Ilya S. Senatorov
- Sonam Raj (ORCID: https://orcid.org/0000-0002-3633-2299)
- Joel M. Bowman (ORCID: https://orcid.org/0000-0001-9692-2672)
- Yasmine C. Abbey
- Brian J. Capaldo (ORCID: https://orcid.org/0000-0003-1244-8884)
- Aian Neil Alilin
- Xiaohu Zhang (ORCID: https://orcid.org/0000-0002-0579-1636)
- Crystal McKnight (ORCID: https://orcid.org/0000-0003-2964-1728)
- Kathleen Kelly
- Paul Shinn
Institutions
- National Institutes of Health (US)
- University of Washington (US)
- National Cancer Institute (US)
- National Center for Advancing Translational Sciences (US)
- Center for Cancer Research (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1016/j.xcrm.2024.101868
- Citations
- 4
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 1.68
Funders
- U.S. Department of Defense
- Prostate Cancer Foundation
- Frederick National Laboratory for Cancer Research
- National Institutes of Health
- National Cancer Institute
- National Center for Advancing Translational Sciences
- DOD Prostate Cancer Research Program