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

Cancer Res. 2022 Jun 6;82(11):2110-2123. doi: 10.1158/0008-5472.CAN-21-3565.


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 TGFβ 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.

Trial registration: ClinicalTrials.gov NCT02452008 NCT03751436 NCT03900884.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Androgen Receptor Antagonists / pharmacology
  • Antineoplastic Agents* / pharmacology
  • Benzamides
  • Cell Line, Tumor
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Drug Resistance, Neoplasm / genetics
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Nitriles / therapeutic use
  • Phenylthiohydantoin
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / genetics
  • Prostatic Neoplasms, Castration-Resistant* / pathology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptors, Androgen / metabolism


  • Androgen Receptor Antagonists
  • Antineoplastic Agents
  • Benzamides
  • Homeodomain Proteins
  • Nitriles
  • PRRX2 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Androgen
  • Phenylthiohydantoin
  • enzalutamide

Associated data

  • ClinicalTrials.gov/NCT02452008
  • ClinicalTrials.gov/NCT03751436
  • ClinicalTrials.gov/NCT03900884