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

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

doi:10.1016/j.xcrm.2024.101868

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

Cell Rep Med. 2024 Dec 17;5(12):101868. doi: 10.1016/j.xcrm.2024.101868. Epub 2024 Dec 9.

Authors

Ilya S Senatorov¹, Joel Bowman¹, Keith H Jansson¹, Aian Neil Alilin¹, Brian J Capaldo¹, Ross Lake¹, Morgan Riba¹, Yasmine C Abbey¹, Crystal Mcknight², Xiaohu Zhang², Sonam Raj¹, Michael L Beshiri¹, Paul Shinn², Holly Nguyen³, Craig J Thomas⁴, Eva Corey³, Kathleen Kelly⁵

Affiliations

¹ Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
² Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
³ Department of Urology, University of Washington, Seattle, WA, USA.
⁴ Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA; Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, NIH, Bethesda, MD, USA.
⁵ Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA. Electronic address: [email protected].

PMID: 39657662
DOI: 10.1016/j.xcrm.2024.101868

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.

Keywords: BIRC3; HNF1A; apoptosis; docetaxel; drug resistance; organoid; pharmacology; prostate cancer; xenograft.

Published by Elsevier Inc.

MeSH terms

Animals
Apoptosis* / drug effects
Baculoviral IAP Repeat-Containing 3 Protein / genetics
Baculoviral IAP Repeat-Containing 3 Protein / metabolism
Bridged-Ring Compounds / pharmacology
Bridged-Ring Compounds / therapeutic use
Cell Line, Tumor
Docetaxel / pharmacology
Docetaxel / therapeutic use
Drug Resistance, Neoplasm* / drug effects
Drug Resistance, Neoplasm* / genetics
Gene Expression Regulation, Neoplastic / drug effects
Hepatocyte Nuclear Factor 1-alpha* / genetics
Hepatocyte Nuclear Factor 1-alpha* / metabolism
Humans
Male
Organoids / drug effects
Organoids / metabolism
Organoids / pathology
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Prostatic Neoplasms, Castration-Resistant* / genetics
Prostatic Neoplasms, Castration-Resistant* / metabolism
Prostatic Neoplasms, Castration-Resistant* / pathology
Taxoids* / pharmacology
Taxoids* / therapeutic use

Substances

Taxoids
Hepatocyte Nuclear Factor 1-alpha
taxane
HNF1A protein, human
Baculoviral IAP Repeat-Containing 3 Protein
Bridged-Ring Compounds
Docetaxel