Crosstalk of LKB1 and KEAP1 mutations in driving growth of lung adenocarcinoma
LKB1 和 KEAP1 突变的串扰驱动肺腺癌的生长
基本信息
- 批准号:9897626
- 负责人:
- 金额:$ 40.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-15 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:5&apos-AMP-activated protein kinaseAdenocarcinomaAdenocarcinoma CellAffectAnimalsAntioxidantsAutomobile DrivingCell LineCell ProliferationCell SurvivalCellsCollaborationsDataDefectDrug Metabolic DetoxicationGene MutationGene SilencingGeneticGenetically Engineered MouseGrowthHistologicHomeostasisHumanImpairmentIn VitroKnock-outKnowledgeLeadLungLung AdenocarcinomaLung NeoplasmsMalignant NeoplasmsMalignant neoplasm of lungMetabolicMetabolic PathwayMetabolic stressModelingMolecularMusMutateMutationNADPNon-Small-Cell Lung CarcinomaNutrientOncogenicOxidation-ReductionPathway interactionsProteinsReactionReactive Oxygen SpeciesResistanceRoleSTK11 geneSignal TransductionStressThe Cancer Genome AtlasTransgenic MiceUp-Regulationcell growthenergy balanceexpectationimprovedin vivoinhibitor/antagonistloss of function mutationlung tumorigenesismetabolomicsmortalitymouse modelmutantneoplastic cellnew therapeutic targetnovelpre-clinicalpublic health relevanceresponsesmall moleculestable isotopetranscriptomicstumortumor growth
项目摘要
DESCRIPTION (provided by applicant): Nearly 25% of lung adenocarcinomas (LuAD) have deletions or inactivating mutations of the gene for LKB1. In response to metabolic stress, wildtype LKB1 promotes catabolic reactions for generating ATP and conserving antioxidant (NADPH and GSH) levels. Since LKB1 counteracts ROS resulting from metabolic stress, the inactivation of this gene in cancer seems to be contrary to expectations, and indeed, LKB1-deficient cells are relatively resistant to oncogenic transformation and sensitive to metabolic stress. TCGA sequencing data revealed that ~ 50% of LKB1-mutant LuAD also harbor a Kelch-ECH associated protein 1 (KEAP1) mutation. Can the impaired ability of LKB1-deficient cells to adapt to nutrient and metabolic stress be overcome by parallel loss of KEAP1? Our preliminary studies revealed that combined loss of Lkb1 and Keap1 decrease ROS and dramatically enhances tumor growth (histologically, adenocarcinomas), and mortality in KrasG12D driven mouse model of lung cancer. Even in the absence of oncogenic Kras signaling, Keap1-/-Lkb1-/- animals form tumors in the lungs with long latency. Importantly, LKB1-deficient cells showed impaired ability to adapt to metabolic stress in the absence of Nrf2 pathway activation, but this defect was rescued by simultaneous loss of Keap1 signaling. KEAP1 mutations lead to gain of NRF2 function in NSCLC that drives antioxidant pathways and metabolic alterations. We hypothesize that KEAP1 mutations in LKB1 mutated lung adenocarcinoma cells causes gain of NRF2 for ROS detoxification and metabolic pathway alterations, which are critical for tumor cell survival. To exploit the vulnerability of this adaptation, we hypothesize that inhibiting NRF2 in tumors with loss of LKB1 and KEAP1 will decrease tumor growth due to metabolic stress. Specific aim 1 will determine if selective loss of Keap1 signaling in Lkb1 deficient lung cells maintains cellular redox homeostasis and promotes lung tumorigenesis. We have developed mouse models with selective deletion of Lkb1 and Keap1 (with or without oncogenic stress - KrasG12D), transgenic mice expressing Nrf2 with activating mutation combined with Lkb1 deletion as well as LKB1 mutant human lung adenocarcinoma cell lines with gain of Nrf2 or loss of Keap1 function. Specific aim 2 will determine the mechanisms by which loss of Keap1 signaling cooperates with Lkb1 signaling for metabolic alterations to provide survival advantage. Transcriptomic and stable isotope resolved metabolomics studies will be performed. Specific aim 3 will determine if disruption of Nrf2 signaling in our mouse models of SA 1 will decrease tumor growth and improve survival using genetic as well as small molecule approach. In addition to genetic knockout of Nrf2, our preliminary studies have shown the efficacy of a novel small molecule (developed in collaboration with NCATS) for inhibiting NRF2 in vitro and in which will be explored for its potential for targeting the Nrf2 pathway in treating LKB1-mutant cancers. These studies will (a) provide the molecular understanding of why 50% of LKB1 loss coexist with KEAP1 mutations in LuAD (b) create the preclinical knowledge essential for targeting this cooperation.
描述(由申请人提供):近25%的肺腺癌(LuAD)具有LKB 1基因的缺失或失活突变。响应于代谢应激,野生型LKB 1促进分解代谢反应以产生ATP并保持抗氧化剂(NADPH和GSH)水平。由于LKB 1抵消了由代谢应激引起的ROS,该基因在癌症中的失活似乎与预期相反,事实上,LKB 1缺陷细胞对致癌转化具有相对抗性,对代谢应激敏感。TCGA测序数据显示,约50%的LKB 1突变型LuAD也携带Kelch-ECH相关蛋白1(KEAP 1)突变。LKB 1缺陷细胞适应营养和代谢应激的能力受损是否可以通过KEAP 1的平行丢失来克服?我们的初步研究表明,Lkb 1和Keap 1的联合缺失降低了ROS,并显著增强了KrasG 12 D驱动的肺癌小鼠模型中的肿瘤生长(组织学上为腺癌)和死亡率。即使在没有致癌Kras信号的情况下,Keap 1-/-Lkb 1-/-动物也会在肺中形成肿瘤,潜伏期很长。重要的是,LKB 1缺陷细胞在Nrf 2通路激活的情况下表现出适应代谢应激的能力受损,但这种缺陷通过同时失去Keap 1信号传导而得以挽救。KEAP 1突变导致NSCLC中NRF 2功能的获得,从而驱动抗氧化途径和代谢改变。我们假设LKB 1突变的肺腺癌细胞中的KEAP 1突变导致NRF 2的获得,用于ROS解毒和代谢途径改变,这对肿瘤细胞存活至关重要。为了利用这种适应的脆弱性,我们假设在LKB 1和KEAP 1缺失的肿瘤中抑制NRF 2将减少由于代谢应激引起的肿瘤生长。具体目标1将确定Lkb 1缺陷肺细胞中Keap 1信号传导的选择性丧失是否维持细胞氧化还原稳态并促进肺肿瘤发生。我们已经开发了选择性缺失Lkb 1和Keap 1的小鼠模型(有或没有致癌应激-KrasG 12 D),表达Nrf 2的转基因小鼠与激活突变结合Lkb 1缺失,以及LKB 1突变的人肺腺癌细胞系与Nrf 2的增益或Keap 1功能的损失。具体目标2将确定Keap 1信号传导的丧失与Lkb 1信号传导合作进行代谢改变以提供生存优势的机制。将进行转录组学和稳定同位素分辨代谢组学研究。具体目标3将确定在我们的SA 1小鼠模型中Nrf 2信号传导的破坏是否会使用遗传以及小分子方法降低肿瘤生长并改善存活。除了Nrf 2的基因敲除之外,我们的初步研究还显示了一种新型小分子(与NCATS合作开发)在体外抑制NRF 2的功效,并将探索其在治疗LKB 1突变型癌症中靶向Nrf 2途径的潜力。这些研究将(a)提供为什么LuAD中50%的LKB 1丢失与KEAP 1突变共存的分子理解(B)创建针对这种合作所必需的临床前知识。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
S-nitrosocysteine and glutathione depletion synergize to induce cell death in human tumor cells: Insights into the redox and cytotoxic mechanisms.
- DOI:10.1016/j.freeradbiomed.2020.08.026
- 发表时间:2020-11-20
- 期刊:
- 影响因子:7.4
- 作者:Knany A;Engelman R;Hariri HA;Biswal S;Wolfenson H;Benhar M
- 通讯作者:Benhar M
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Shyam Biswal其他文献
Shyam Biswal的其他文献
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$ 40.34万 - 项目类别:
Crosstalk of LKB1 and KEAP1 mutations in driving growth of lung adenocarcinoma
LKB1 和 KEAP1 突变的串扰驱动肺腺癌的生长
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9262182 - 财政年份:2016
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9098288 - 财政年份:2016
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Crosstalk of LKB1 and KEAP1 mutations in driving growth of lung adenocarcinoma
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