Fatty acid metabolism regulates ferroptosis in mutant KRAS lung cancer

脂肪酸代谢调节突变 KRAS 肺癌的铁死亡

• 批准号: 10363789
• 负责人: PIER Paolo SCAGLIONI
• 金额: $ 40.2万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10363789
• 关键词: Acyl Coenzyme A; Acyltransferase; Address; Affect; Apoptosis; Biochemical Pathway; Bioenergetics; Cancer Etiology; Cancer cell line; Cell Death; Cell Survival; Cell physiology; Cells; Cessation of life; Coenzyme A; Coenzyme A Ligases; Data; Dependence; Development; Drug Targeting; Enzymes; Essential Fatty Acids; Esters; Extinction (Psychology); FASN gene; Family member; Fatty Acids; Fatty-acid synthase; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Human; Image; Immunotherapy; In Vitro; Intracellular Accumulation of Lipids; Iron; KRAS2 gene; Knowledge; Lead; Lecithin; Lipid Peroxides; Lysophosphatidylcholines; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Metabolic; Metabolism; Minority; Mutation; Non-Small-Cell Lung Carcinoma; Nonesterified Fatty Acids; Oncogenes; Oncogenic; Oral; Outcome; Oxidative Stress; Oxides; PLA2G4C gene; Patients; Peroxides; Phase II Clinical Trials; Phenotype; Phospholipase A2; Phospholipids; Pre-Clinical Model; Process; Prognosis; Property; Proto-Oncogenes; Reaction; Reactive Oxygen Species; Resolution; Role; Signal Transduction; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Testing; Therapeutic; Transgenic Mice; Validation; airway epithelium; antitumor effect; cancer cell; cancer therapy; effective therapy; experimental study; fatty acid metabolism; feeding; in vivo; inhibitor; innovation; insight; lipid metabolism; lipidome; lipidomics; long chain fatty acid; lung cancer cell; lung tumorigenesis; mouse model; mutant; novel; novel therapeutics; peroxidation; programs; reconstitution; repaired; tandem mass spectrometry; therapeutic target; therapy resistant; tumor; tumorigenesis

SUMMARY Lung cancer (LC) is the leading cause of cancer related death in the USA and in the world. Activating mutations of the proto-oncogene KRAS (mutant KRAS, KM thereafter) occur in ~30% of non-small cell lung cancer (NSCLC). These cancers are associated with an aggressive phenotype, resistance to therapy and poor outcome. Expression of KM in the respiratory epithelium is sufficient to initiate lung tumorigenesis. Furthermore, KM is required for the maintenance of established tumors. These observations establish KM as a high priority drug target. Only a minority of patients with KM-driven LC benefit from therapy, including immunotherapy or KRASG12C inhibitors. Accordingly, patients with KMLC have a poor prognosis. Hence, there is an urgent need for effective therapies for KMLC. Cancer cells undergo oncogene-directed metabolic reprogramming in order to meet the energetic and biosynthetic challenges of cell survival, growth and proliferation. It has been proposed that these changes are critical for the maintenance of established cancers. Indeed, we found that extinction of KM in LC of transgenic mice leads to the perturbation of several metabolic networks including fatty acid (FA) synthesis. To determine the contribution of lipid metabolism to KM-driven LC, we characterized the lipidome of KMLC with high resolution mass spectrometry, matrix-assisted laser desorption/ionization imaging MS (MALDI-IMS) and functional experiments. Our preliminary data indicate that KM upregulates Fatty acid synthase (FASN) and the synthesis of FA to repair peroxided phospholipids (PL) damaged by reactive oxygen species (ROS). FASN is often upregulated in cancer, however its role has remained elusive. We found that inhibition of FASN with TVB-3664, a first in class FASN inhibitor (FASNi), induces ferroptosis, a form of iron- and ROS- dependent programmed cell death characterized by the accumulation of lipid peroxides both in vitro and in vivo in preclinical models of KMLC. Lipidomics analysis and functional experiments suppressing ACSL3, LPCAT3 and PLA2G4C strongly suggest that in KMLC, FA serve a prosurvival function by feeding the Lands cycle, the main process that remodels the peroxided acyl chains of PL, deflecting ferroptosis. These observations support the hypothesis that KMLC depends on FA to evade ferroptosis and to promote tumorigenesis. We propose to test this hypothesis with a multifaceted approach that employs KM transgenic mice, panels of LC cells lines, functional and lipidomics experiments. it is worth noting that our group provided the rationale for a phase II clinical trial of TVB-2640, a FASNi derivative, in patients with KMLC (NCI identifier NCT03808558). We anticipate that these studies will contribute to a better understanding of cellular metabolic networks required for KM driven tumorigenesis, providing the framework for the development of novel cancer therapies.

总结 肺癌（LC）是美国和世界上癌症相关死亡的主要原因。激活 原癌基因KRAS突变（突变型KRAS，此后为KM）发生在约30%的非小细胞肺 癌症（NSCLC）。这些癌症与侵袭性表型、对治疗的抗性和不良反应有关。 结果。KM在呼吸道上皮中的表达足以启动肺肿瘤发生。 此外，KM是维持已建立的肿瘤所必需的。这些观察将知识管理确定为 一个高度优先的药物目标只有少数KM驱动LC患者从治疗中获益，包括 免疫疗法或KRASG 12 C抑制剂。因此，KMLC患者预后不良。因此，我们认为， 迫切需要有效的治疗KMLC的方法。 癌细胞经历癌基因指导的代谢重编程，以满足能量和 细胞存活、生长和增殖的生物合成挑战。有人建议，这些变化是 对于维持已形成的癌症至关重要。事实上，我们发现转基因小鼠LC中KM的灭绝 在小鼠中的代谢导致包括脂肪酸（FA）合成在内的几种代谢网络的扰动。 为了确定脂质代谢对KM驱动的LC的贡献，我们表征了KMLC的脂质组， 采用高分辨率质谱、基质辅助激光解吸/电离成像MS（MALDI-IMS）和 功能性实验我们的初步数据表明，KM上调脂肪酸合成酶（Fatty acid synthase，FATCH）， FA的合成以修复由活性氧（ROS）损伤的过氧化磷脂（PL）。 在癌症中，FXR通常上调，但其作用仍然难以捉摸。我们发现， 与TVB-3664（FASNi类中的第一种FASNi抑制剂）一起使用的FASNi可诱导铁凋亡，这是一种铁和ROS- 依赖性程序性细胞死亡的特点是脂质过氧化物在体外和体内的积累， KMLC的临床前模型。脂质组学分析和抑制ACSL 3、LPCAT 3和 PLA 2G 4C强烈表明，在KMLC中，FA通过喂养Lands循环，主要的 重塑PL的过氧化酰基链，使铁凋亡偏转的过程。 这些观察结果支持了KMLC依赖FA来逃避铁凋亡和 促进肿瘤发生。我们建议测试这一假设与多方面的方法，采用知识管理 转基因小鼠、LC细胞系组、功能和脂质组学实验。值得注意的是， TVB-2640是一种FASNi衍生物， KMLC（NCI标识符NCT 03808558）。我们期望这些研究将有助于更好地理解 知识管理驱动的肿瘤发生所需的细胞代谢网络，为开发提供框架 新型癌症治疗方法。