PERTURBATION OF THE AMINO ACID STRESS RESPONSE PATHWAY EXPOSES A METABOLIC VULNERABILITY IN MULTIPLE AGGRESSIVE CANCER SUBTYPES

Cancer cells frequently experience nutrient limitation and depend on adaptive stress-response pathways to maintain metabolic homeostasis. Here, we show that pharmacological perturbation of amino acid stress signaling exerts broad anti-tumor activity across multiple aggressive malignancies, including acute lymphoblastic leukemia, acute myeloid leukemia, triple-negative breast cancer, ovarian cancer, and neuroblastoma. Sensitivity to pathway modulation is associated with a chronic stress-adapted metabolic state marked by constitutive amino acid response signaling, elevated NFE2L2 expression, and reduced mitochondrial abundance despite evidence of efficient oxidative metabolism. Mechanistically, we demonstrate that the ATP-competitive compound GCN2-IN-6 does not phenocopy genetic GCN2 suppression and exhibits context-dependent effects on the amino acid stress response. Nevertheless, tumors experiencing chronic metabolic stress remain exquisitely sensitive to disruption of this adaptive network, regardless of whether signaling is perturbed through canonical inhibition or paradoxical activation. Collectively, our findings identify chronic metabolic stress adaptation as an actionable vulnerability and establish off-balancing amino acid stress signaling as a therapeutic strategy across multiple cancer types