Higher GCN2 Expression Is Associated with Favorable Clinical and Genomic Features in Advanced Prostate Cancer
ESMO 2026
Bicky Thapa, Michelle Weitz, Nilansh Kataria, Supriya Peshin, Gabriella Rickards, Suen Wesley, Praful K Ravi, Atish D. Choudhury, John Guittar, Lisa Macera, Metamia Ciampricotti, Mary-Ellen Taplin
Background
Preclinical studies show that the amino acid stress-sensing kinase GCN2 (EIF2AK4) is constantly active and essential for growth in hormone-sensitive (HSPC) and castration-resistant prostate cancer (CRPC) models. However, the significance of GCN2 expression in advanced prostate cancer (PCa) remains unclear. We explored the relationship between GCN2 expression, clinical features, genomic characteristics, immune microenvironment, and outcomes in patients with advanced PCa.
Methods
We used the Tempus Lens Platform to query a de-identified, multimodal database for male patients with metastatic PCa and Tempus xT (DNA, 648 genes) and xR (RNA, whole transcriptome) testing with tumor purity ≥30%. GCN2 expression was divided into tertiles (low, mid, high). Clinical characteristics, somatic alterations, tumor mutational burden (TMB), and immune markers were compared across groups. Real-world time to next treatment (rwTTNT) and overall survival (rwOS) were measured from 1L treatment start and evaluated using multivariable weighted Cox models reporting average hazard ratios (aHR).
Results
Of 8,456 patients (61% HSPC, 16% CRPC, 23% unknown), high GCN2 correlated with fewer CRPC cases (7.8% vs 27% in low GCN2), more HSPC (69% vs 51%), and more samples from primary tumors (76% vs 49%; all p<0.001). Low GCN2 tumors had enriched high-risk alterations: TP53 (39.2% vs 31.0% in high GCN2), RB1 (14.1% vs 3.3%), APC (11.8% vs 5.7%), and AR (11.0% vs 3.8%; all q<0.001). Higher GCN2 linked to a "cold" immune phenotype: lower TMB, reduced M1 macrophages, Tregs, and decreased PDCD1, CTLA4, LAG3, and FOXP3 expression (all p<0.001). Higher continuous GCN2 was significantly associated with longer rwTTNT (n=2,077; aHR 0.78, 95% CI 0.62–0.99, p=0.044), but not rwOS (n=2,847; aHR 0.93, 95% CI 0.71-1.21, p=0.580).
Conclusions
Higher GCN2 expression is associated with less aggressive clinical and genomic features and longer rwTTNT, but a more immunologically cold microenvironment. These findings highlight GCN2’s complex biological role and suggest its potential utility as a biomarker for disease stratification and tumor immunogenicity.
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