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Updated: Jun 14, 2026
Pooled CRISPR-Based Genetic Screens in Mammalian Cells
Published on: September 4, 2019
CRISPR genome-wide screening identifies PAK1 as a critical driver of ARSI cross-resistance in prostate cancer
Haojie Chen1, Keqin Dong2, Jie Ding3
1Department of Urology, School of Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, 200092, China; Department of Urology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China.
Abstract:
Next-generation androgen receptor signaling inhibitors (ARSIs), such as enzalutamide (Enza) and darolutamide (Daro), are initially effective for the treatment of advanced prostate cancer (PCa) and castration-resistant prostate cancer (CRPC). However, patients often relapse and develop cross-resistance, which consequently makes drug resistance an inevitable cause of CRPC-related mortality. By conducting a comprehensive analysis of GEO datasets, CRISPR genome-wide screening results, ATAC-seq data, and RNA-seq data, we systemically identified PAK1 as a significant contributor to ARSI cross-resistance due to the activation of the PAK1/RELA/hnRNPA1/AR-V7 axis. Inhibition of PAK1 followed by suppression of NF-κB pathways and AR-V7 expression effectively overcomes ARSI cross-resistance. Our findings indicate that PAK1 represents a promising therapeutic target gene for the treatment of ARSI cross-resistant PCa patients in the clinic. STATEMENT OF SIGNIFICANCE: PAK1 drives ARSI cross-resistance in prostate cancer progression.
Insights
Protein kinase 1 (PAK1) drives resistance to advanced prostate cancer therapies. Inhibiting PAK1 overcomes this resistance by targeting the PAK1/RELA/hnRNPA1/AR-V7 pathway, offering a new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Next-generation androgen receptor signaling inhibitors (ARSIs) like enzalutamide and darolutamide are initial treatments for advanced and castration-resistant prostate cancer (CRPC).
- Tumor relapse and cross-resistance to ARSIs are common, leading to mortality in CRPC patients.
- Understanding the mechanisms of ARSI cross-resistance is crucial for developing effective therapies.
Purpose of the Study:
- To identify key molecular drivers of ARSI cross-resistance in prostate cancer.
- To elucidate the signaling pathways involved in ARSI cross-resistance.
- To evaluate PAK1 as a potential therapeutic target for overcoming ARSI resistance.
Main Methods:
- Comprehensive analysis of public datasets including Gene Expression Omnibus (GEO) datasets.
- Utilized CRISPR genome-wide screening, ATAC-seq, and RNA-seq data.
- Investigated the role of the PAK1/RELA/hnRNPA1/AR-V7 axis in ARSI resistance.
Main Results:
- Identified Protein Kinase 1 (PAK1) as a significant contributor to ARSI cross-resistance.
- Demonstrated that PAK1 activates the RELA/hnRNPA1/AR-V7 axis, promoting resistance.
- Showed that inhibiting PAK1 effectively suppresses NF-κB pathways and AR-V7 expression, overcoming ARSI cross-resistance.
Conclusions:
- PAK1 plays a critical role in driving ARSI cross-resistance in prostate cancer.
- Targeting PAK1, along with NF-κB pathways and AR-V7, offers a promising strategy to overcome treatment resistance.
- PAK1 is a potential therapeutic target for patients with ARSI-resistant prostate cancer.
