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.
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.