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Transcriptional profiling clarifies a program of enzalutamide extreme non-response in lethal prostate cancer
Anbarasu Kumaraswamy1,2, Ya-Mei Hu3,4, Joel A Yates1,2
1Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Abstract:
The androgen receptor inhibitor enzalutamide is one of the principal treatments for metastatic prostate cancer. Most patients respond. However, a subset is primary refractory. Seeking to understand enzalutamide extreme non-response (ENR), we analyzed RNA-sequencing in biopsies from men treated prospectively on an enzalutamide clinical trial. We focused on those with ENR (progression within 3 months) vs. long-term response (progression after 24 months). We identified an ENR program linked to proliferation, epithelial-to-mesenchymal transition, and stemness. High expression of this program in additional datasets was independently linked to poor tumor control with AR targeting but favorable tumor control with docetaxel, another standard treatment. CDK2 was implicated in the ENR program. CDK2 suppression reduced the ENR program and viability of ENR program-high prostate cancer models. The ENR gene program is predictive of non-response to AR targeting. Patients whose tumors harbor this program may be good candidates for docetaxel or CDK2 inhibitor clinical trials.
Insights
Enzalutamide non-response in prostate cancer is linked to a specific gene program. This program predicts treatment outcomes and suggests alternative therapies like docetaxel or CDK2 inhibitors for non-responding patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Enzalutamide is a key treatment for metastatic prostate cancer.
- A subset of patients exhibits primary resistance to enzalutamide, termed enzalutamide extreme non-response (ENR).
Purpose of the Study:
- To investigate the molecular mechanisms underlying enzalutamide extreme non-response (ENR) in metastatic prostate cancer.
- To identify predictive biomarkers for treatment response and explore alternative therapeutic strategies.
Main Methods:
- RNA-sequencing analysis of tumor biopsies from patients treated with enzalutamide.
- Comparison of gene expression profiles between patients with ENR and long-term responders.
- Validation in independent patient datasets and in vitro functional studies.
Main Results:
- An "ENR gene program" associated with proliferation, epithelial-to-mesenchymal transition, and stemness was identified.
- High expression of this program predicted poor response to androgen receptor (AR) targeting therapies.
- Conversely, high ENR program expression correlated with favorable outcomes with docetaxel treatment.
- CDK2 was implicated in the ENR program, and its suppression reduced ENR program activity and cancer cell viability.
Conclusions:
- The identified ENR gene program is a predictive biomarker for non-response to AR-targeting therapies in prostate cancer.
- Patients with tumors exhibiting this program may benefit from alternative treatments such as docetaxel.
- Targeting CDK2 presents a potential therapeutic strategy for patients with enzalutamide-refractory prostate cancer.
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