Nutrient availability dictates cancer metabolism-based therapeutic responses of non-oncology drugs

Metabolic deregulation is a major hallmark of cancer, therefore, interventions that modify tumor nutrient availability are considered attractive adjuvants for improving clinical outcomes for cancer patients. Much work remains, however, in clarifying how the nutritional status of each patient can affect the metabolic vulnerability of drugs and inform individual medication guidelines. Working toward the goal of oncometabolic precision medicine, we introduce CM-SLP (cancer metabolism-based synthetic lethality platform), a high-throughput screening platform that explores the metabolic vulnerability of non-oncology drugs induced by altered nutrient availability and predicts the potential synthetic lethal interactions with either hyper- or hypo-nutrient conditions. We present promising CM-SLP candidates, such as propafenone and biguanides, as representative non-oncology drugs that cooperatively enhance cytotoxicity via dysregulated metabolic pathways. Furthermore, identifying mTOR and Hippo pathways as mediators of combined propafenone/hypoglycemia or biguanides/hypoglycemia treatments, respectively, we were able to circumvent the need for dietary interventions by administering the mTOR or TEAD inhibitors to induce energy stress and cancer cell death. Together, CM-SLP represents a critical step toward integrating metabolic profiling into precision oncology, offering novel therapeutic avenues tailored to individual patient needs.