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Updated: Jul 25, 2025
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Genomic Profiling of Metastatic Castration-Resistant Prostate Cancer Samples Resistant to Androgen Receptor Pathway
Naoual Menssouri1, Loïc Poiraudeau1, Carole Helissey2
1Inserm U981, Molecular Predictors and New Targets in Oncology, Gustave Roussy Cancer Campus, Paris-Saclay University, Villejuif, France.
Purpose:
The androgen receptor axis inhibitors (ARPI; e.g., enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown.
Experimental Design:
In the prospective trial MATCH-R (NCT02517892), 59 patients with mCRPC underwent whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 patients with mCRPC underwent biopsy at time of resistance. The objectives were to identify genomic alterations associated with resistance to ARPIs as well as to describe clonal evolution. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher exact tests.
Results:
WES analysis indicated that no single-gene genomic alterations were strongly associated with primary resistance. RNA-seq analysis showed that androgen receptor (AR) gene alterations and expression levels were similar between responders and nonresponders. RNA-based pathway analysis found that patients with primary resistance had a higher Hedgehog pathway score, a lower AR pathway score and a lower NOTCH pathway score than patients with a response. Subclonal evolution and acquisition of new alterations in AR-related genes or neuroendocrine differentiation are associated with acquired resistance. ARPIs do not induce significant changes in the tumor transcriptome of most patients; however, programs associated with cell proliferation are enriched in resistant samples.
Conclusions:
Low AR activity, activation of stemness programs, and Hedgehog pathway were associated with primary ARPIs' resistance, whereas most acquired resistance was associated with subclonal evolution, AR-related events, and neuroendocrine differentiation. See related commentary by Slovin, p. 4323.
Insights
Mechanisms of resistance to androgen receptor axis inhibitors (ARPI) in metastatic castration-resistant prostate cancer (mCRPC) are complex. Primary resistance involves low AR activity and activated Hedgehog pathway, while acquired resistance stems from clonal evolution and neuroendocrine differentiation.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Androgen receptor axis inhibitors (ARPI) are standard treatment for metastatic castration-resistant prostate cancer (mCRPC).
- Patient response to ARPIs varies, and mechanisms of primary and acquired resistance are not fully understood.
Purpose of the Study:
- To investigate genomic and transcriptomic alterations associated with primary and acquired resistance to ARPIs in mCRPC.
- To describe clonal evolution in patients developing resistance to ARPIs.
Main Methods:
- Prospective trial (MATCH-R) involving whole-exome sequencing (WES) and RNA sequencing (RNA-seq) of mCRPC samples.
- Analysis of pre-treatment and on-treatment resistance biopsies.
- Statistical association testing for genomic and transcriptomic alterations with ARPI resistance.
Main Results:
- No single-gene alterations strongly predicted primary resistance; AR gene alterations were similar in responders and non-responders.
- Primary resistance was associated with higher Hedgehog pathway activity, lower AR pathway activity, and lower NOTCH pathway activity.
- Acquired resistance correlated with subclonal evolution, new AR-related gene alterations, and neuroendocrine differentiation. Proliferation pathways were enriched in resistant tumors.
Conclusions:
- Primary resistance to ARPIs in mCRPC is linked to low AR activity, stemness programs, and Hedgehog pathway activation.
- Acquired resistance is primarily driven by subclonal evolution, AR-related events, and neuroendocrine differentiation.
