Identifying Potential Mechanisms of Enzalutamide Resistance in Prostate Cancer using a Genome-wide CRISPR activation Screen
PublicDownloadable Content
Download PDFAndrogen receptor pathway inhibitors are the mainstay treatment for advanced prostate cancer, but resistance is common. Here, we used a CRISPR activation screen to identify genes that promote enzalutamide resistance in the metastatic castration-sensitive prostate cancer cell line LNCaP. We found that activation of the TGF-β target gene, PRRX2, promoted enzalutamide resistance. PRRX2 expression is highest in double negative prostate cancer (DNPC) patients and a PRRX2-related gene signature identified a subset of DNPC patients with lower overall survival. PRRX2 expressing cells showed alterations in the CDK4/6/Rb/E2F and BCL2 pathways. Accordingly, CDK4/6 and BCL2 inhibitors sensitized PRRX2-expressing enzalutamide-resistant tumors to enzalutamide. High PRRX2 expression/signature in prostate cancer merit investigation as markers of enzalutamide resistance that could be reversed with CDK4/6 and BCL2 inhibitors.
- Creator
- DOI
- Subject
- Language
- Alternate Identifier
- http://dissertations.umi.com/northwestern:16015
- etdadmin_upload_898469
- Date created
- Resource type
- Rights statement
Relationships
Items
Thumbnail | Title | Date Uploaded | Visibility | Actions |
---|---|---|---|---|
File | 2022-06-22 | Northwestern |