Overcoming cisplatin resistance by targeting fatty acid metabolism

摘要 化疗是减少肺癌局部复发和远处转移的重要手段。 晚期口腔鳞状细胞癌（OCSCC）患者。虽然是一种古老的药物， 在美国，顺铂形成了OCSCC化疗方案的支柱。以来 OCSCC顺铂反应是高度可变的，开发新的克服方法至关重要。 顺铂耐药。获得“高风险”TP 53突变是OCSCC生存的关键驱动因素 和顺铂耐药性;然而，TP 53的突变不能被有效地直接靶向。我们 初步数据表明，靶向脂质代谢，可以克服顺铂耐药性， 与“高危”TP 53突变相关。 突变导致的p53功能丧失：1）损害线粒体储备能力，2） 增加糖酵解通量和3）增加细胞对氧化应激的适应。这些影响 与顺铂耐药性增强平行发生。脂肪酸氧化（FAO）和脂肪酸 合成（FAS）是细胞氧化应激反应的关键驱动因素，因为它们是 负责大部分还原当量（NADH、NADPH、FADH 2）的产生和/或 利用率在目标1中，我们将测试高危TP 53突变对FAO/FAS比率的影响， 评估FAO抑制剂在改善高风险患者顺铂反应方面的相对有效性 TP 53突变。 在目标2中，我们将使用同样基于脂质的TP 53突变肿瘤的平行方法 新陈代谢.铁凋亡（程序性细胞死亡）是由氧化应激和依赖性 对脂质过氧化的影响我们发现，铁凋亡激动剂可以在两种野生型细胞中引起细胞死亡， 和突变型TP 53 OCSCC。在这个目的中，我们将测试铁凋亡激动剂是否可以克服 顺铂耐药性与细胞系和PDX肿瘤中的“高风险”TP 53突变相关。 尽管继续寻找更有效的替代品，顺铂仍然是主要的 用于晚期OCSCC全身性药物。直到其他探员证明 和令人信服的优势，我们必须制定更有效的战略， 克服顺铂耐药性。这些战略还必须考虑到 TP 53突变对OCSCC治疗反应的影响。在目前的提案中，我们利用 关于代谢靶向的大量初步数据，并提出利用一种方法 基于脂肪酸代谢，我们认为这两个方面的致命 疾病

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.