Overcoming cisplatin resistance by targeting fatty acid metabolism

摘要 化疗是减少局部复发和远处转移的关键手段 晚期口腔鳞状细胞癌患者。虽然是一种古老的药物， 顺铂构成了美国OCSCC化疗方案的主干。自.以来 OCSCC顺铂的反应是高度可变的，开发新的克服方法至关重要 顺铂耐药。获得“高危”TP53突变是口腔鳞癌生存的关键驱动因素 和顺铂耐药；然而，TP53的突变不能有效地直接靶向。我们的 初步数据表明，以脂代谢为靶点可以克服顺铂耐药性 与“高危”的TP53突变有关。 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)增强细胞对氧化应激的适应。这些影响 与顺铂耐药性增强同时发生。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 负责大部分减排当量(NADH、NADPH、FADH2)的产生和/或 利用率。在目标1中，我们将测试高危TP53突变对粮农组织/Fas比率和 评价粮农组织抑制剂改善高危患者顺铂反应的相对有效性 TP53基因突变。 在目标2中，我们将对同样基于脂质预测的TP53突变肿瘤使用一种平行的方法。 新陈代谢。铁下垂(程序性细胞死亡)由氧化应激激活，并依赖于 关于脂质过氧化。我们发现铁下垂激动剂可以导致两种野生型的细胞死亡。 和突变体TP53 OCSCC。在这个目标中，我们将测试铁下垂激动剂是否可以克服 顺铂耐药与细胞系和PDX肿瘤中高危的TP53突变有关。 尽管继续寻找更有效的替代品，顺铂仍然是主要的选择。 用于高级OCSCC的全身药剂。直到其他特工证明清楚 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。这些战略还必须考虑到压倒性的 TP53突变对口腔鳞癌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，并建议利用一种方法 基于脂肪酸新陈代谢的预测，我们认为它解决了致命的 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.