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.

概括 肺癌（LC）是美国和世界上与癌症有关的主要原因。激活 原始癌基因KRAS的突变（此后突变KRAS，KM）发生在约30％的非小细胞肺中 癌症（NSCLC）。这些癌症与侵略性表型有关，对治疗的抵抗力和差 结果。 KM在呼吸上皮中的表达足以启动肺部肿瘤发生。 此外，维持已建立的肿瘤需要KM。这些观察结果将KM确定为 高优先药物目标。只有KM驱动LC的患者中只有少数受益于治疗，包括 免疫疗法或KRASG12C抑制剂。因此，KMLC患者的预后较差。因此， 迫切需要对KMLC进行有效的疗法。 癌细胞进行癌基指导的代谢重编程，以满足能量和 细胞存活，生长和增殖的生物合成挑战。有人提出这些变化是 维持既定的癌症至关重要。确实，我们发现KM在转基因的LC中的灭绝 小鼠导致几个代谢网络（包括脂肪酸（FA）合成）的扰动。 为了确定脂质代谢对KM驱动LC的贡献，我们表征了KMLC的脂质组 具有高分辨率的质谱法，基质辅助激光解吸/电离成像MS（MALDI-IM）和 功能实验。我们的初步数据表明，KM上调脂肪酸合酶（FASN）和 FA的合成以修复被活性氧（ROS）损坏的过氧化磷脂（PL）。 FASN通常在癌症中上调，但是其作用仍然难以捉摸。我们发现抑制 FASN具有TVB-3664，是FASN类抑制剂（FASNI）的第一个，诱导铁肉芽作用，这是一种铁和Ros-的形式 依赖的程序性细胞死亡的特征是体外和体内脂质过氧化物的积累 KMLC的临床前模型。脂质组学分析和功能实验抑制ACSL3，LPCAT3和 PLA2G4C强烈建议在KMLC中，FA通过喂食土地周期来发挥创造作用 重塑PL的过氧酰基链，从而偏转铁铁蛋白的过程。 这些观察结果支持以下假设：KMLC取决于FA以逃避铁铁病和 促进肿瘤发生。我们建议通过采用KM的多方面方法检验这一假设 转基因小鼠，LC细胞系，功能和脂肪组学实验。值得注意的是，我们的 小组提供了针对Fasni衍生物TVB-2640的II期临床试验的基本原理。 KMLC（NCI标识符NCT03808558）。我们预计这些研究将有助于更好地理解 KM驱动肿瘤发生所需的细胞代谢网络，为发育提供了框架 新型癌症疗法。