Glucose deprivation induces cancer cell death through oncogene overdose

Metabolic rewiring is a hallmark of cancer, commonly exemplified by the Warburg effect and increased glucose dependence. The cytotoxic effects of glucose withdrawal are typically attributed to energy depletion or impaired anabolic processes. While oncogenic drivers shape metabolic reprogramming during tumorigenesis, and therapy resistance induces further metabolic alterations, it remains unclear whether metabolic perturbations can directly modulate oncogenic signalling. Here, we show that glucose withdrawal induces cell death in EGFR-, BRAF-, or PI3K-driven cancer cells through oncogene overdose rather than metabolic failure. Transcriptomic and phosphoproteomic analyses reveal that glucose depletion sensitizes specific transcripts and phosphopeptides to oncogene inhibition, indicating that metabolic stress rewires oncogenic function. Mechanistically, pyruvate depletion promotes the accumulation of reactive oxygen species (ROS), triggering oncogene superactivation and JNK-dependent cell death, accompanied by dysregulation of mitotic and cytokinesis regulators. Together, these findings have uncovered a critical function of the Warburg effect in preventing toxic levels of oncogene activation, highlighting the importance of metabolic context when targeting oncogenic signalling in cancer.