EZH2 Inhibition Induces a Metabolic Stress Response Sensitizing TNBC to Glutaminase Targeting

EZH2, the catalytic subunit of Polycomb Repressive Complex II, is overexpressed and associated with poor prognosis in triple-negative breast cancer (TNBC). Although EZH2 inhibition induces significant changes in chromatin landscapes and gene expression, it has a limited impact on the growth of TNBC models, suggesting adaptive compensatory mechanisms. Here, we demonstrate that EZH2 inhibition leads to the accumulation of misfolded proteins and double-stranded RNA (dsRNA), triggering an essential integrated stress response (ISR) through PKR and PERK activation. By inducing ISR-mediated ATF4 activation, EZH2 inhibition enhances amino acid flux and promotes glutaminolysis, in turn activating mTOR signaling to support TNBC cell survival. Pharmacological targeting of this metabolic adaptation with a glutaminase (GLS) inhibitor in combination with EZH2 inhibition significantly impairs TNBC cell proliferation and tumor growth. These findings reveal a stress-driven metabolic adaptation that sustains TNBC survival upon EZH2 blockade and highlight inhibition of this pathway as a strategy to enhance the efficacy of EZH2 inhibitors in TNBC.