Metabolic Adaptations to the Integrated Stress Response Enable TNBC Survival Upon EZH2 Inhibition [PDX1915_polyA_RNAseq]

So far, inhibiting EZH2 has shown limited effectiveness in slowing TNBC progression, suggesting the activation of compensatory mechanisms. Here, we demonstrate that EZH2 inhibition in TNBC induces the accumulation of double-stranded RNA and misfolded proteins, activating the integrated stress response (ISR) via the PKR/PERK-eIF2α pathway.

We identify Activating Transcription Factor 4 (ATF4) as a key ISR effector, driving metabolic changes, including increased amino acid uptake and enhanced glutamine-dependant metabolism. Targeting this ISR-ATF4-mediated metabolic response using a glutaminase inhibitor in combination with EZH2 inhibition significantly impairs TNBC cell proliferation and tumor progression. These findings uncover an adaptive metabolic stress response that enables TNBC survival upon EZH2 inhibition and highlight the potential of targeting ISR-driven metabolic adaptations to enhance EZH2 inhibitor efficacy in TNBC.