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

基本信息

  • 批准号:
    10544159
  • 负责人:
  • 金额:
    $ 39.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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)是美国乃至全世界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% 的非小细胞肺中 癌症(非小细胞肺癌)。这些癌症与侵袭性表型、治疗耐药性和较差的预后有关。 结果。 KM 在呼吸道上皮中的表达足以引发肺部肿瘤发生。 此外,KM对于维持已形成的肿瘤是必需的。这些观察结果将 KM 确立为 高度优先的药物靶点。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, KMLC 迫切需要有效的治疗方法。 癌细胞经历癌基因引导的代谢重编程,以满足能量和能量的需求。 细胞存活、生长和增殖的生物合成挑战。有人提议这些改变是 对于已确定的癌症的维持至关重要。事实上,我们发现转基因的 LC 中 KM 消失了。 小鼠的饮食会导致多种代谢网络的扰动,包括脂肪酸 (FA) 的合成。 为了确定脂质代谢对 KM 驱动的 LC 的贡献,我们对 KMLC 的脂质组进行了表征 具有高分辨率质谱、基质辅助激光解吸/电离成像 MS (MALDI-IMS) 和 功能实验。我们的初步数据表明 KM 上调脂肪酸合酶 (FASN) 合成 FA 来修复被活性氧 (ROS) 损坏的过氧化磷脂 (PL)。 FASN 在癌症中经常上调,但其作用仍然难以捉摸。我们发现抑制 FASN 与 TVB-3664 是同类首个 FASN 抑制剂 (FASNi),可诱导铁死亡(铁和 ROS- 的一种形式) 依赖性程序性细胞死亡,其特征是脂质过氧化物在体外和体内的积累 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 强烈建议,在 KMLC 中,FA 通过供给土地循环来发挥促生存功能,土地循环是主要的 重塑 PL 过氧化酰基链的过程,使铁死亡偏转。 这些观察结果支持这样的假设:KMLC 依赖 FA 来避免铁死亡并 促进肿瘤发生。我们建议通过采用知识管理的多方面方法来检验这一假设 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,我们的 小组提供了 TVB-2640(一种 FASNi 衍生物)在患有以下疾病的患者中进行 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 驱动的肿瘤发生所需的细胞代谢网络,为开发提供框架 新的癌症疗法。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

PIER Paolo SCAGLIONI其他文献

PIER Paolo SCAGLIONI的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('PIER Paolo SCAGLIONI', 18)}}的其他基金

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
  • 财政年份:
    2022
  • 资助金额:
    $ 39.4万
  • 项目类别:
Characterization and drug targeting of the PML tumor suppressor in lung cancer
肺癌 PML 肿瘤抑制因子的表征和药物靶向
  • 批准号:
    8265668
  • 财政年份:
    2009
  • 资助金额:
    $ 39.4万
  • 项目类别:
Characterization and drug targeting of the PML tumor suppressor in lung cancer
肺癌 PML 肿瘤抑制因子的表征和药物靶向
  • 批准号:
    8490689
  • 财政年份:
    2009
  • 资助金额:
    $ 39.4万
  • 项目类别:
Characterization and drug targeting of the PML tumor suppressor in lung cancer
肺癌 PML 肿瘤抑制因子的表征和药物靶向
  • 批准号:
    7736061
  • 财政年份:
    2009
  • 资助金额:
    $ 39.4万
  • 项目类别:
Characterization and drug targeting of the PML tumor suppressor in lung cancer
肺癌 PML 肿瘤抑制因子的表征和药物靶向
  • 批准号:
    8193127
  • 财政年份:
    2009
  • 资助金额:
    $ 39.4万
  • 项目类别:
Post-transcriptional regulation of PML function
PML 功能的转录后调控
  • 批准号:
    7107156
  • 财政年份:
    2005
  • 资助金额:
    $ 39.4万
  • 项目类别:
Post-transcriptional regulation of PML function
PML 功能的转录后调控
  • 批准号:
    7339972
  • 财政年份:
    2005
  • 资助金额:
    $ 39.4万
  • 项目类别:
Post-transcriptional regulation of PML function
PML 功能的转录后调控
  • 批准号:
    7269404
  • 财政年份:
    2005
  • 资助金额:
    $ 39.4万
  • 项目类别:
Post-transcriptional regulation of PML function
PML 功能的转录后调控
  • 批准号:
    7467999
  • 财政年份:
    2005
  • 资助金额:
    $ 39.4万
  • 项目类别:
Post-transcriptional regulation of PML function
PML 功能的转录后调控
  • 批准号:
    7668423
  • 财政年份:
    2005
  • 资助金额:
    $ 39.4万
  • 项目类别:

相似海外基金

Greasing endocytosis in plants - understanding the role of S-acylation in receptor kinase function and internalisation
植物中的润滑内吞作用 - 了解 S-酰化在受体激酶功能和内化中的作用
  • 批准号:
    BB/Y003756/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.4万
  • 项目类别:
    Research Grant
Ghrelin de-acylation inhibitors as novel compounds for Parkinson's dementia
生长素释放肽去酰化抑制剂作为治疗帕金森痴呆症的新型化合物
  • 批准号:
    MR/Y503435/1
  • 财政年份:
    2024
  • 资助金额:
    $ 39.4万
  • 项目类别:
    Research Grant
S-acylation-dependent regulation of cytokine receptor signaling and cardiac maladaptation
细胞因子受体信号传导和心脏适应不良的 S-酰化依赖性调节
  • 批准号:
    10561406
  • 财政年份:
    2023
  • 资助金额:
    $ 39.4万
  • 项目类别:
Comprehensive analysis of acidic patch binder using histone acylation catalysts
使用组蛋白酰化催化剂综合分析酸性贴片粘合剂
  • 批准号:
    22KJ1113
  • 财政年份:
    2023
  • 资助金额:
    $ 39.4万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
S-Acylation of transmembrane proteins in the early secretory pathway
早期分泌途径中跨膜蛋白的 S-酰化
  • 批准号:
    BB/X001504/1
  • 财政年份:
    2023
  • 资助金额:
    $ 39.4万
  • 项目类别:
    Research Grant
N-terminal acylation and sorting of Helicobacter pylori lipoproteins and their role in host response to infection
幽门螺杆菌脂蛋白的 N 末端酰化和分选及其在宿主感染反应中的作用
  • 批准号:
    10584620
  • 财政年份:
    2022
  • 资助金额:
    $ 39.4万
  • 项目类别:
The Molecular Mechanisms of Glycolytic Enzyme S-acylation in Neurons
神经元糖酵解酶S-酰化的分子机制
  • 批准号:
    576016-2022
  • 财政年份:
    2022
  • 资助金额:
    $ 39.4万
  • 项目类别:
    Alexander Graham Bell Canada Graduate Scholarships - Master's
Anti-CRISPR-mediated Acylation and Bioreversible Esterification for Precision Genome Editing
用于精准基因组编辑的抗 CRISPR 介导的酰化和生物可逆酯化
  • 批准号:
    10657417
  • 财政年份:
    2022
  • 资助金额:
    $ 39.4万
  • 项目类别:
High Throughput Screen for Inhibitors of the YEATS2 Histone Acylation Reader
YEATS2 组蛋白酰化酶抑制剂的高通量筛选
  • 批准号:
    10389517
  • 财政年份:
    2022
  • 资助金额:
    $ 39.4万
  • 项目类别:
Roles of KAT8 complexes in governing histone acylation and mouse cerebral development
KAT8复合物在控制组蛋白酰化和小鼠大脑发育中的作用
  • 批准号:
    RGPIN-2019-07122
  • 财政年份:
    2022
  • 资助金额:
    $ 39.4万
  • 项目类别:
    Discovery Grants Program - Individual
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了