Pharmacologic Targeting of ZNF281 Suppresses Metastatic Prostate Cancer Beyond Androgen Receptor Dependence
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Metastatic prostate cancer remains a lethal disease, with most treatments focusing on the androgen receptor (AR) axis. We identified the zinc finger protein 281 (ZNF281) as a previously unrecognized driver of metastatic prostate cancer that promotes both AR-related transcriptional output and distinct AR-independent tumor-promoting pathways. It increases AR expression and acts as a coactivator to promote AR transcriptional activity. Independent of AR, ZNF281 promotes prostate cancer by upregulating SMURF1 to sustain tumor growth and by promoting SNAIL-mediated metastasis. We developed an orally bioavailable, ZNF281 Interfering Molecule (Oral ZIM) that disrupts its DNA binding and AR protein interaction. Knockout of ZNF281 as well as treatment with oral ZIM potently inhibited prostate cancer growth and metastasis in orthotopic xenograft models of castration-sensitive and castration-resistant prostate cancers (without detectable systemic toxicity), and ZIM outperformed enzalutamide treatment in patient-derived prostate cancer organoids.
Significance
This study reveals the previously uncharacterized of ZNF281 in promoting androgen receptor–dependent transcription and androgen receptor-independent proliferative and metastatic programs in prostate cancer, advances understanding of disease progression across different androgen receptor expression statuses, and establishes pharmacologic ZNF281 inhibition as a therapeutic strategy for metastatic prostate cancer.
