Glucose deprivation induces cancer cell death through oncogene overdose

Glucose deprivation induces cancer cell death through oncogene overdose | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Glucose deprivation induces cancer cell death through oncogene overdose Igor Vivanco, Khine Nyein Myint, Alice Harbery, Eleftherios Kostaras, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9347608/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract 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. Biological sciences/Cancer Biological sciences/Cancer/Cancer metabolism Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9347608","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":619171258,"identity":"cab0cfaf-7130-4a4f-b17b-360a5425cd96","order_by":0,"name":"Igor 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