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Updated: Jul 7, 2026
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced
Thomas C Westbrook1, Xiangnan Guan2, Eva Rodansky1
1Division of Hematology and Oncology, Department of Internal Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Abstract:
The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients' progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.
Insights
Enzalutamide resistance in metastatic castration-resistant prostate cancer (CRPC) can involve lineage plasticity. A predictive gene signature in baseline biopsies indicates higher risk for this resistance and poor outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Enzalutamide is a key treatment for metastatic castration-resistant prostate cancer (CRPC).
- Mechanisms of enzalutamide resistance include lineage plasticity, where tumors become less AR-dependent.
- Understanding resistance drivers is crucial for improving CRPC treatment outcomes.
Purpose of the Study:
- To investigate transcriptomic changes associated with enzalutamide resistance in CRPC.
- To identify predictive biomarkers for lineage plasticity-mediated resistance.
- To explore the role of E2F1 and stemness pathways in treatment resistance.
Main Methods:
- RNA sequencing of matched tumor biopsies from CRPC patients before and after enzalutamide treatment (n=21).
- Analysis of transcriptomic data to identify changes related to treatment and resistance.
- Validation of gene signatures in independent patient cohorts and xenograft models.
Main Results:
- Enzalutamide treatment did not induce significant sustained transcriptomic changes in most CRPC patients.
- Three patients exhibited lineage plasticity at progression, characterized by reduced AR dependency.
- Baseline biopsies from patients with lineage plasticity showed high activation of E2F1 and stemness pathways.
- A specific gene signature in baseline biopsies predicted lineage plasticity and was associated with poor survival.
Conclusions:
- Lineage plasticity is a resistance mechanism in a subset of CRPC patients treated with enzalutamide.
- E2F1 and stemness pathways are implicated in the development of lineage plasticity.
- A baseline gene signature can identify CRPC patients at high risk for enzalutamide resistance and adverse outcomes, guiding therapeutic strategies.
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