Aberrant CRTC activation as a unique vulnerability of lung cancer with LKB1 inactivation
CRTC 异常激活是 LKB1 失活肺癌的独特弱点
基本信息
- 批准号:10558734
- 负责人:
- 金额:$ 33.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:AgingAmino AcidsBehaviorBiologyCREB1 geneCRISPR/Cas technologyCancer BiologyCancer EtiologyCancer PatientCell NucleusCellsCessation of lifeChIP-seqDataDevelopmentDominant-Negative MutationEpithelial CellsEventFamilyGenesGenetic TranscriptionGenetically Engineered MouseGrowthHumanINSL4 geneIndividualKRAS2 geneKnock-outKnowledgeLungMalignant NeoplasmsMalignant neoplasm of lungMediatingMediatorMetabolismMolecularMutationNon-Small-Cell Lung CarcinomaPathway interactionsPeptidesPhosphorylationProtein DephosphorylationProtein-Serine-Threonine KinasesProteinsProteomicsPublishingResearchRoleSTK11 geneSerineSignal InductionSignal PathwaySignal TransductionSystemTestingTherapeuticTherapeutic InterventionTranscription CoactivatorTransgenic MiceTumor Suppressor GenesTumor Suppressor ProteinsXenograft Modelcancer cellcell growtheffective therapygene functiongene networkgenetic profilingin vivoinhibitorinsightlung cancer cellmalignant phenotypemolecular subtypesmortalitymouse modelnovel therapeutic interventionpreventprogramsprotein complexsalt-inducible kinasetargeted treatmenttherapeutic targettranscription factortranscriptome sequencingtumorigenesis
项目摘要
Project Summary/Abstract
Lung cancer is the leading cause of cancer deaths worldwide and there is an urgent need for effective
treatment. Comprehensive genetic profiling has revealed that the LKB1 (STK11) tumor suppressor gene is
frequently altered in non–small cell lung cancer (NSCLC), a major form of lung cancer. Lung cancer with LKB1
inactivation has distinct biology and behaviors; however, no targeted therapies are currently available for this
unique, prevalent molecular subtype of lung cancer. While it is traditionally challenging to target an inactive or
absent tumor suppressor, its effector pathways likely present rational target opportunities for therapeutic
intervention.
The LKB1 gene encodes a serine/threonine kinase regulating cell growth, polarity, and metabolism. An
important function of LKB1 is negatively regulating a family of three CREB transcriptional co-activators (CRTC1,
2,3), which have crucial roles in metabolism, aging and cancer. We previously discovered that LKB1 loss causes
enhanced levels of dephosphorylated CRTCs that subsequently translocate to the nucleus and promote
transcription of CREB-dependent genes in cancer cells. However, the importance of this aberrantly active CRTC-
CREB signaling axis and its underlying mechanisms in lung cancer remain poorly characterized and such
knowledge will be crucial in uncovering new therapeutic strategies. Therefore, our proposed research is aimed
to bridge this significant gap by elucidating this LKB1 inactivation-induced signaling for its significance and
mechanisms in lung cancer. Building on our published and preliminary data, we hypothesize that aberrant CRTC
activation is a core driver event that underlies LKB1 loss in lung malignancies, presenting a unique vulnerability
of LKB1-inactivated lung cancers. This hypothesis will be tested by two specific aims. Aim 1 will elucidate the
functional significance of aberrantly activated CRTC-CREB signaling in lung cancers with LKB1 inactivation, and
Aim 2 will define the mechanisms of aberrant CRTC-CREB activation in lung cancers with LKB1 inactivation.
The successful completion of these proposed studies will uncover new mechanistic and functional insights into
aberrant CRTC activation in the development and progression of LKB1-inactivated lung cancer. We anticipate
that these efforts will validate CRTCs as a therapeutic target, reveal novel therapeutic strategies, and contribute
to our mechanistic understanding of the biology of cancer with LKB1 inactivation.
项目摘要/摘要
肺癌是全球癌症死亡的主要原因,迫切需要有效
治疗。综合基因分析表明,LKB1(STK11)抑制基因是
在非小细胞肺癌(NSCLC)中经常改变,这是一种主要形式的肺癌。 LKB1的肺癌
失活具有独特的生物学和行为。但是,目前尚无靶向疗法
肺癌的独特,普遍的分子亚型。虽然传统上是针对非活动或
没有肿瘤抑制器,其效应途径可能是治疗的合理目标机会
干涉。
LKB1基因编码丝氨酸/苏氨酸激酶,可调节细胞生长,极性和代谢。一个
LKB1的重要功能是负调节三个CREB转录共激活因子的家族(CRTC1,
2,3),在代谢,衰老和癌症中具有至关重要的作用。我们以前发现LKB1损失原因
增强的去磷酸化的CRTC水平随后转移到核并促进
癌细胞中CREB依赖基因的转录。但是,这种异常活跃的crtc-的重要性
CREB信号轴及其在肺癌中的潜在机制的表征仍然很差,此类
知识对于揭示新的治疗策略至关重要。因此,我们拟议的研究针对
通过阐明该LKB1灭活诱导的信号的意义和
肺癌的机制。在我们已发布和初步数据的基础上,我们假设CRTC异常
激活是一个核心驱动事件,它是肺部恶性肿瘤中LKB1损失的基础
LKB1灭活的肺癌。该假设将通过两个具体目标来检验。 AIM 1将阐明
LKB1失活的肺癌中异常激活的CRTC-CREB信号传导的功能显着性,并且
AIM 2将定义LKB1失活的肺癌中异常CRTC-CREB激活的机制。
这些提出的研究的成功完成将发现新的机械和功能见解
LKB1灭活的肺癌的发育和进展中的异常CRTC激活。我们期待
这些努力将验证CRTC作为治疗目标,揭示新的治疗策略并做出贡献
为了我们对LKB1失活的癌症生物学的机械理解。
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)
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Lizi Wu的其他文献
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{{ truncateString('Lizi Wu', 18)}}的其他基金
Aberrant CRTC activation as a unique vulnerability of lung cancer with LKB1 inactivation
CRTC 异常激活是 LKB1 失活肺癌的独特弱点
- 批准号:
10334407 - 财政年份:2019
- 资助金额:
$ 33.54万 - 项目类别:
A novel noncoding RNA and human lung cancers with inactivated LKB1 signaling
一种新型非编码 RNA 与 LKB1 信号失活的人类肺癌
- 批准号:
8881623 - 财政年份:2015
- 资助金额:
$ 33.54万 - 项目类别:
Signaling and targeting of CRTC1-MAML2 fusion oncoprotein in salivary gland tumor
CRTC1-MAML2融合癌蛋白在唾液腺肿瘤中的信号传导和靶向
- 批准号:
8696318 - 财政年份:2014
- 资助金额:
$ 33.54万 - 项目类别:
Signaling and Targeting of CRTC1-MAML2 Fusion Oncoprotein in Salivary Gland
唾液腺中 CRTC1-MAML2 融合癌蛋白的信号传导和靶向
- 批准号:
10439473 - 财政年份:2014
- 资助金额:
$ 33.54万 - 项目类别:
Signaling and targeting of CRTC1-MAML2 fusion oncoprotein in salivary gland tumor
CRTC1-MAML2融合癌蛋白在唾液腺肿瘤中的信号传导和靶向
- 批准号:
8907995 - 财政年份:2014
- 资助金额:
$ 33.54万 - 项目类别:
Signaling and Targeting of CRTC1-MAML2 Fusion Oncoprotein in Salivary Gland
唾液腺中 CRTC1-MAML2 融合癌蛋白的信号传导和靶向
- 批准号:
10208855 - 财政年份:2014
- 资助金额:
$ 33.54万 - 项目类别:
Signaling and Targeting of CRTC1-MAML2 Fusion Oncoprotein in Salivary Gland
唾液腺中 CRTC1-MAML2 融合癌蛋白的信号传导和靶向
- 批准号:
10672248 - 财政年份:2014
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$ 33.54万 - 项目类别:
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- 资助金额:
$ 33.54万 - 项目类别:
Transformation of Epithelial Cell by E6 Oncogene
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7317800 - 财政年份:2003
- 资助金额:
$ 33.54万 - 项目类别:
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