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Updated: Jun 5, 2025

Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
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Castrate-resistant prostate cancer response to taxane is determined by an HNF1-dependent apoptosis resistance circuit

Ilya S Senatorov1, Joel Bowman1, Keith H Jansson1

  • 1Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.

Cell Reports. Medicine
|December 10, 2024
PubMed

Insights

Researchers identified a key driver of taxane resistance in metastatic castrate-resistant prostate cancer (mCRPC). Targeting cellular inhibitor of apoptosis protein 2 (cIAP2) with LCL161 shows promise for treating resistant mCRPC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Metastatic castrate-resistant prostate cancer (mCRPC) is a complex disease requiring novel therapeutic strategies.
  • Taxanes are a vital treatment for mCRPC, but resistance limits their efficacy.
  • Biomarker discovery is crucial for advancing targeted therapies in mCRPC.

Purpose of the Study:

  • To identify molecular drivers of taxane resistance in patient-derived castrate-resistant prostate cancer (CRPC) organoids.
  • To screen a drug library against diverse CRPC models to find potential therapeutic targets.
  • To investigate the role of HNF1 homeobox A (HNF1A) in mediating taxane resistance.

Main Methods:

  • High-throughput drug screening of 78 compounds against 30 patient-derived CRPC organoids.
  • Quantitative response measurement and transcriptomic analysis of organoid models.
  • Investigating the dependency of taxane resistance on cellular inhibitor of apoptosis protein 2 (cIAP2) in HNF1A+ models.

Main Results:

  • HNF1 homeobox A (HNF1A) was identified as a driver of taxane resistance in mCRPC.
  • Taxane resistance was frequently dependent on cellular inhibitor of apoptosis protein 2 (cIAP2).
  • Monotherapy with the cIAP2 inhibitor LCL161 effectively treated docetaxel-resistant HNF1A+ mCRPC models.

Conclusions:

  • HNF1A plays a significant role in the transcriptional program of taxane resistance in mCRPC.
  • Targeting cIAP2 with LCL161 represents a potential therapeutic strategy for taxane-resistant mCRPC.
  • These findings can inform future clinical trial designs for mCRPC treatment.
Keywords:
BIRC3HNF1Aapoptosisdocetaxeldrug resistanceorganoidpharmacologyprostate cancerxenograft

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