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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.
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.
