Androgen receptor condensates drive gastric cancer through SWI/SNF-mediated chromatin remodeling and create a therapeutic vulnerability
TL;DR
These findings establish AR phase separation as a fundamental mechanism driving GC pathogenesis and propose co-targeting AR condensates and chromatin remodeling as a translatable therapeutic strategy.
Abstract
Gastric cancer (GC) remains a leading cause of cancer mortality, with epidemiological patterns indicative of androgen signaling involvement. We establish androgen receptor (AR) as a pivotal oncogenic factor in GC and provide preclinical validation for its therapeutic targeting. AR expression was significantly elevated in GC tissues and correlated with adverse prognosis across ten independent cohorts ( n = 1740). We demonstrate that AR promotes tumor proliferation in cell and organoid models. Mechanistically, AR undergoes liquid-liquid phase separation (LLPS) to form biomolecular condensates that recruit switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complexes. This process enhances chromatin accessibility and activates oncogenic transcriptional programs. Disruption of AR condensates—achieved either by deleting its intrinsically disordered region 2 (IDR2) or pharmacological inhibition with the AR antagonist enzalutamide (Enza)—suppressed GC growth. Combinatorial treatment with Enza and the SWI/SNF ATPase degrader AU-15330 elicited potent synergistic antitumor effects in GC cell lines, organoids, and xenografts. Furthermore, we developed an AR LLPS activity signature enabling prognostic stratification and potential therapeutic guidance. Collectively, these findings establish AR phase separation as a fundamental mechanism driving GC pathogenesis and propose co-targeting AR condensates and chromatin remodeling as a translatable therapeutic strategy.