ABSTRACT Chemotherapy is a critical tool in reducing locoregional recurrence and distant metastasis in patients with advanced oral cavity squamous cell carcinoma (OCSCC). Although an old drug, cisplatin forms the backbone of chemotherapy regimens for OCSCC in the United States. Since OCSCC cisplatin response is highly variable, it is critical to develop novel means of overcoming cisplatin resistance. Acquisition of “high-risk” TP53 mutations is a critical driver of OCSCC survival and cisplatin resistance; however, mutations of TP53 cannot be effectively targeted directly. Our preliminary data indicate, that targeting of lipid metabolism, could overcome cisplatin resistance associated with “high-risk” TP53 mutations. Loss of p53 function through mutation: 1) impairs mitochondrial reserve capacity, 2) increases glycolytic flux and 3) increases cellular adaptation to oxidative stress. These effects occur in parallel with enhanced resistance to cisplatin. Fatty acid oxidation (FAO) and fatty acid synthesis (FAS) are critical drivers of the cellular oxidative stress response since they are responsible for a large portion of reducing equivalent (NADH, NADPH, FADH2) generation and/or utilization. In Aim 1 we will test the impact of high-risk TP53 mutations on the FAO/FAS ratio and evaluate the relative effectiveness of FAO inhibitors in improving cisplatin response in high-risk TP53 mutations. In Aim 2 we will use a parallel approach to TP53 mutant tumors also predicated on lipid metabolism. Ferroptosis (programmed cell death) is activated by oxidative stress and dependent on lipid peroxidation. We found that ferroptosis agonists can generate cell death in both wild-type and mutant TP53 OCSCC. In this Aim we will test whether ferroptosis agonists can overcome cisplatin resistance associated with “high-risk” TP53 mutations in cell lines and PDX tumors. Despite a continued search for more effective alternatives, cisplatin remains the mainstay systemic agent for use in advanced OCSCC. Until such time as other agents demonstrate clear and convincing superiority, it is imperative that we develop more effective strategies which can overcome cisplatin resistance. These strategies must also take into account the overwhelming impact of TP53 mutations on OCSCC response to treatment. In the current proposal, we leverage substantial preliminary data regarding metabolic targeting and propose to utilize an approach predicated on fatty acid metabolism which we believe addresses both aspects of this deadly disease.