Nutrient Availability Dictates Cancer Metabolism-Based Therapeutic Responses to Nononcology Drugs.

Metabolic dysregulation is a major hallmark of cancer, making interventions that modify tumor nutrient availability attractive adjuvants for improving clinical outcomes for patients with cancer. Clarifying how the nutritional status of individual patients affects the metabolic vulnerability of tumors to drugs is needed to inform personalized treatment guidelines. Working toward the goal of oncometabolic precision medicine, we developed the cancer metabolism-based synthetic lethality platform (CM-SLP), a high-throughput screening platform that explores the metabolic vulnerability of cancer cells to nononcology drugs induced by altered nutrient availability and predicts potential synthetic lethal interactions with nutrient conditions. Promising CM-SLP candidates included propafenone and biguanides as representative nononcology drugs that cooperatively enhanced cytotoxicity via dysregulated metabolic pathways. Furthermore, the mTOR and Hippo pathways mediated the response to combined propafenone/hypoglycemia or biguanides/hypoglycemia treatments, respectively, and mTOR or TEAD inhibitors circumvented the need for dietary interventions to enhance cancer cell death. Together, these results indicate that CM-SLP represents a promising approach for integrating metabolic profiling into precision oncology, offering therapeutic avenues tailored to individual patient needs. SIGNIFICANCE: A high-throughput screening approach investigating drug vulnerabilities dependent on nutrient status supports repurposing FDA-approved compounds as metabolically informed therapies for next-generation oncometabolic precision medicine.