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Updated: Jun 9, 2026
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Identification of selective SWI/SNF dependencies in enzalutamide-resistant prostate cancer
Bengul Gokbayrak1,2, Umut Berkay Altintas3, Shreyas Lingadahalli3
1Koc University Research Centre for Translational Medicine (KUTTAM), Istanbul, Turkey.
Abstract:
Enzalutamide is a potent second-generation antiandrogen commonly used to treat hormone-sensitive and castration-resistant prostate cancer (CRPC) patients. While initially effective, the disease almost always develops resistance. Given that many enzalutamide-resistant tumors lack specific somatic mutations, there is strong evidence that epigenetic factors can cause enzalutamide resistance. To explore how resistance arises, we systematically test all epigenetic modifiers in several models of castration-resistant and enzalutamide-resistant prostate cancer with a custom epigenetic CRISPR library. From this, we identify and validate SMARCC2, a core component of the SWI/SNF complex, that is selectivity essential in enzalutamide-resistant models. We show that the chromatin occupancy of SMARCC2 and BRG1 is expanded in enzalutamide resistance at regions that overlap with CRPC-associated transcription factors that are accessible in CRPC clinical samples. Overall, our study reveals a regulatory role for SMARCC2 in enzalutamide-resistant prostate cancer and supports the feasibility of targeting the SWI/SNF complex in late-stage PCa.
Insights
Epigenetic factors drive resistance to enzalutamide, a prostate cancer drug. Researchers identified SMARCC2 as crucial for this resistance, suggesting new therapeutic targets for advanced prostate cancer.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Enzalutamide is a key treatment for prostate cancer, including castration-resistant prostate cancer (CRPC).
- Tumor resistance to enzalutamide frequently develops, often without specific genetic mutations, indicating a role for epigenetic mechanisms.
- Understanding these epigenetic drivers is crucial for overcoming treatment resistance.
Purpose of the Study:
- To systematically investigate the role of epigenetic modifiers in the development of enzalutamide resistance in prostate cancer.
- To identify specific epigenetic factors that are essential for enzalutamide-resistant castration-resistant prostate cancer (CRPC).
Main Methods:
- Utilized a custom epigenetic CRISPR library to screen all epigenetic modifiers in models of CRPC and enzalutamide-resistant prostate cancer.
- Employed chromatin immunoprecipitation sequencing (ChIP-seq) to assess the occupancy of key proteins.
- Analyzed publicly available CRPC clinical sample data.
Main Results:
- Identified and validated SMARCC2, a component of the SWI/SNF complex, as selectively essential in enzalutamide-resistant prostate cancer models.
- Demonstrated expanded chromatin occupancy of SMARCC2 and BRG1 in enzalutamide-resistant cells.
- Observed overlap of SMARCC2/BRG1 occupancy with accessible CRPC-associated transcription factor binding sites in clinical samples.
Conclusions:
- SMARCC2 plays a significant regulatory role in enzalutamide-resistant prostate cancer.
- The findings support targeting the SWI/SNF complex as a potential therapeutic strategy for late-stage prostate cancer.
