A study out today in @NatureGenet from Core Investigator @LukeGilbertSF, @li_haolong & others identifies PTGES3 as a critical regulator of androgen receptor (AR) protein levels in prostate cancer, revealing a potential new target for tumors that become treatment-resistant.

The team developed an endogenous AR fluorescent reporter & used genome-wide CRISPRi screens to systematically map genes that control AR protein abundance. PTGES3 was a top hit, but almost nothing was known about its role in prostate cancer.

Through biochemical experiments & structural modeling, researchers showed that PTGES3 binds directly to AR in the nucleus. This binding interaction stabilizes AR protein & is required for AR to activate its target genes.

In clinical findings, high PTGES3 expression predicts worse outcomes in patients treated with drugs like abiraterone & enzalutamide. But loss of PTGES3 blocked tumor growth across multiple models of aggressive, therapy-resistant prostate cancer.

Importantly, PTGES3 is selectively required in AR-driven prostate cancer cells but not AR-independent cancer cells. Unlike targeting HSP90, inhibiting PTGES3 offers a potentially more specific way to block AR without broadly disrupting the heat shock response.