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Understanding Enzalutamide-Resistance Based on a Functional Single-Cell Approach
Changhui Xue1, Hyun-Kyung Ko1, Kasen Shi1
1Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.
The Prostate
|April 11, 2025
Summary
A small subpopulation of prostate cancer cells with low androgen receptor (AR) expression drives resistance to enzalutamide therapy. These AR-low cells are selected and expanded by treatment, leading to castration-resistant prostate cancer (CRPC).
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastatic prostate cancer (PCa) treatment relies on anti-androgen or castration therapies.
- Androgen-dependent PCa (ADPC) often develops resistance, progressing to incurable castration-resistant PCa (CRPC).
- Mechanisms of CRPC emergence from ADPC remain largely unclear.
Purpose of the Study:
- To investigate the transcriptional heterogeneity of ADPC cells.
- To understand the response of ADPC cells to enzalutamide treatment.
- To identify mechanisms of therapy resistance in prostate cancer.
Main Methods:
- Single-cell RNA-sequencing (scRNA-Seq) of LNCaP cells.
- Isolation of androgen receptor low/negative (ARlow/-) cell subpopulations.
- In vitro and in vivo functional assays using xenograft models.
- Single-nucleus RNA-Seq on xenografts.
Main Results:
- A small subpopulation (~10%) of LNCaP cells expressed low or no androgen receptor (ARlow/-).
- ARlow/- cells exhibited distinct transcriptional profiles and pathways associated with CRPC.
- ARlow/- cells demonstrated enzalutamide resistance in vitro and in vivo.
- Enzalutamide treatment selected for ARlow/- cells and de-selected AR-positive (AR+) cells in vivo.
Conclusions:
- A clonal selection and expansion model explains enzalutamide resistance in PCa.
- Pre-existing ARlow/- subpopulations are selected and expanded by anti-androgen therapy.
- Targeting ARlow/- cells may be a strategy to overcome treatment resistance.
