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bioRxiv · 10.1101/2025.09.04.674332

EZH2 Inhibition Induces an Integrated Stress Response Driving Glutamine-Dependent Vulnerability in TNBC

Deblois, G.·Porras, L.·Fukano, M.·Gironne, A.-S.·Quadri, E.·Alzial, G.·Philippeau, H.·Alaessa, Y.·Monast, A.·Gorse, F.·St-Arnaud, M.·De Sa Tavares Russo, M.·MADER, s.·Avizonis, D.·Lemieux, S.·Park, M. M.
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Abstract

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.

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Deblois, G., Porras, L., Fukano, M., Gironne, A.-S., Quadri, E., Alzial, G., Philippeau, H., Alaessa, Y., Monast, A., Gorse, F., St-Arnaud, M., De Sa Tavares Russo, M., MADER, s., Avizonis, D., Lemieux, S., Park, M. M.. 2025-09-09. EZH2 Inhibition Induces an Integrated Stress Response Driving Glutamine-Dependent Vulnerability in TNBC. https://doi.org/10.1101/2025.09.04.674332

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