A Genome-Wide CRISPR Activation Screen Identifies PRRX2 as a Regulator of Enzalutamide Resistance in Prostate Cancer

Yara Rodríguez, Kenji Unno, Mihai I. Truica, Zachary R. Chalmers, Young A Yoo, Rajita Vatapalli, Vinay Sagar, Jindan Yu, Barbara Lysy, Maha H A Hussain, Huiying Han, Sarki A. Abdulkadir*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Androgen receptor (AR) pathway inhibitors are the mainstay treatment for advanced prostate cancer, but resistance to therapy is common. Here, we used a CRISPR activation screen in metastatic castration-sensitive prostate cancer cells to identify genes that promote resistance to AR inhibitors. Activation of the TGFb target gene paired-related homeobox2 (PRRX2) promoted enzalutamide resistance. PRRX2 expression was the highest in double-negative prostate cancer (DNPC), which lack AR signaling and neuroendocrine differentiation, and a PRRX2-related gene signature identified a subset of patients with DNPC with reduced overall survival. PRRX2-expressing cells showed alterations in the CDK4/6/Rb/E2F and BCL2 pathways. Accordingly, treatment with CDK4/6 and BCL2 inhibitors sensitized PRRX2-expressing, castration-resistant tumors to enzalutamide. Overall, PRRX2 was identified as a driver of enzalutamide resistance. The PRRX2 signature merits investigation as a biomarker of enzalutamide resistance in prostate cancer that could be reversed with CDK4/6 and BCL2 inhibitors. Significance: PRRX2 mediates enzalutamide resistance via activation of the E2F and BCL2 pathways, which can be targeted with CDK4/6 and BCL2 inhibitors to reverse resistance.

Original languageEnglish (US)
Pages (from-to)2110-2123
Number of pages14
JournalCancer Research
Volume82
Issue number11
DOIs
StatePublished - Jun 1 2022

Funding

This work was supported by NCI grants P50CA180995, F30CA50248, and F30CA50196 and Prostate Cancer Foundation Challenge Award. The authors thank Dr. Matt Clutter from the Northwestern High-throughput Core facility for helping with the CRISPRa screen design and execution; Dr. Ching Man Wai, Dr. Matthew J. Schipma, and Priyam Patel at the NUSeq Facility for ATAC-seq execution and data analysis; Carolina Ostiguin from the The Robert H. Lurie Comprehensive Cancer Center Flow Cytometry Core for help in flow cytometry analysis; The American Association of University Women (AAUW)–International Fellowship for their support; and all the Abdulkadir lab members for their valuable discussion. Y. Rodríguez reports grants from NCI, Prostate Cancer Foundation Challenge Award and grants from American Association of University Women (AAUW)– International Fellowship during the conduct of the study. M.I. Truica reports grants from NCI during the conduct of the study. V. Sagar reports grants from NCI and grants from Prostate Cancer Foundation Challenge Award outside the submitted work. B. Lysy reports grants from NCI and grants from Prostate Cancer Foundation Challenge Award during the conduct of the study. M. Hussain reports other support from Arvinas, AstraZeneca, Bayer, Genentech, Astellas, RTP, MLI Peer View, AstraZeneca, ReachMD, PrecisCa, Merck, Medscape, Tempus, Janssen, Pfizer, and other support from Novartis outside the submitted work; in addition, M. Hussain has a patent for UM-14437/US-1/PRO issued to IMBIO and a patent for PCT/US2011/ 053233 issued. H. Han reports grants from NIH and grants from Prostate Cancer Foundation Challenge Award during the conduct of the study. S.A. Abdulkadir reports grants from NCI and grants from PCF during the conduct of the study. No disclosures were reported by the other authors.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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