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: 10544159
• 负责人: PIER Paolo SCAGLIONI
• 金额: $ 39.4万
• 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/10544159
• 关键词: Acyl Coenzyme A; Acylation; Acyltransferase; 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; Family member; Fatty Acids; Fatty-acid synthase; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Human; Image; Immunotherapy; In Vitro; Intracellular Accumulation of Lipids; Iron; Knowledge; Lead; Lecithin; Lipid Peroxides; Lysophosphatidylcholines; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Metabolic; Metabolism; Minority; Modeling; Mutation; Non-Small-Cell Lung Carcinoma; Nonesterified Fatty Acids; Oncogenes; Oncogenic; Oral; Outcome; Oxidative Stress; PLA2G4C gene; Patients; Peroxides; Phase II Clinical Trials; Phenotype; Phospholipase A2; Phospholipids; Pre-Clinical Model; Process; Prognosis; Proliferating; 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; coping; 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; 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.

摘要 肺癌(LC)是美国和世界范围内癌症相关死亡的主要原因。正在激活 原癌基因KRAS(突变型KRAS，以下简称KM)突变发生在约30%的非小细胞肺癌中 癌症(NSCLC)。这些癌症与侵袭性表型、对治疗的抵抗力和较差有关。 结果。KM在呼吸道上皮细胞中的表达足以启动肺肿瘤的发生。 此外，KM是维持已建立的肿瘤所必需的。这些观测结果将KM确定为 一个高度优先的毒品目标。只有少数KM驱动的LC患者从治疗中受益，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进行有效的治疗。 癌细胞进行癌基因导向的代谢重编程，以满足能量和 细胞生存、生长和增殖的生物合成挑战。有人提出，这些变化是 对维持已建立的癌症至关重要。的确，我们发现在转基因的LC中KM的消亡 小鼠导致包括脂肪酸(FA)合成在内的几个代谢网络的紊乱。 为了确定脂质代谢在KM驱动的LC中的作用，我们对KMLC的脂质体进行了表征 利用高分辨率质谱仪，基质辅助激光解吸/电离成像质谱仪(MALDI-IMS)和 机能实验。我们的初步数据表明，KM上调脂肪酸合成酶(FASN)和 合成FA以修复被活性氧(ROS)损伤的过氧化磷脂(PL)。 FASN在癌症中经常上调，然而它的作用仍然难以捉摸。我们发现，对大脑的抑制 FASN使用TVB-3664，一种一流的FASN抑制剂(FASNi)，可以诱导铁下垂，一种铁和ROS的形式- 依赖性程序性细胞死亡，其特征是体内和体外的过氧化脂质积聚。 KMLC的临床前模型。抑制ACSL3、LPCAT3和LPCAT3的脂质组学分析和功能实验 PLA2G4C强烈提示，在KMLC中，FA通过供给Lands循环，主要是 改造磷脂过氧化的酰基链，使其偏离铁下垂的过程。 这些观察结果支持这样的假设，即KMLC依赖FA来逃避铁下垂和 促进肿瘤发生。我们建议使用KM的多方面方法来检验这一假设 转基因小鼠，LC细胞系面板，功能和脂质组学实验。值得注意的是，我们的 该小组为TVB-2640的II期临床试验提供了理论基础，TVB-2640是一种FASNi的衍生物，用于 KMLC(NCI标识符NCT03808558)。我们期待这些研究将有助于更好地了解 KM驱动的肿瘤发生所需的细胞代谢网络，为发展提供了框架 新的癌症治疗方法。