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：
10334407
负责人：
Lizi Wu
金额：
$ 33.57万
依托单位：
UNIVERSITY OF FLORIDA
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10334407
关键词：
Aging Amino Acids Behavior Biology CREB1 gene CRISPR/Cas technology Cancer Biology Cancer Etiology Cancer Patient Cell Nucleus Cells Cessation of life ChIP-seq Data Development Dominant-Negative Mutation Epithelial Cells Event Family Genes Genetic Transcription Genetically Engineered Mouse Growth Human INSL4 gene Individual KRAS2 gene Knock-out Knowledge Lung Malignant Neoplasms Malignant neoplasm of lung Mediating Mediator of activation protein Metabolism Molecular Mutation Non-Small-Cell Lung Carcinoma Pathway interactions Peptides Protein-Serine-Threonine Kinases Proteins Proteomics Publishing Research Role STK11 gene Signal Pathway Signal Transduction System Testing Therapeutic Therapeutic Intervention Transcription Coactivator Transgenic Mice Tumor Suppressor Genes Tumor Suppressor Proteins Xenograft Model cancer cell cell growth cell immortalization effective therapy gene function gene network genetic profiling in vivo inhibitor insight lung cancer cell malignant phenotype molecular subtypes mortality mouse model novel therapeutic intervention prevent programs protein complex salt-inducible kinase targeted treatment therapeutic target transcription factor transcriptome sequencing tumorigenesis

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.

项目概要/摘要肺癌是全球癌症死亡的主要原因，迫切需要有效的治疗综合基因分析显示，LKB1 (STK11) 肿瘤抑制基因是。肺癌中 LKB1 在非小细胞肺癌 (NSCLC)（肺癌的一种主要形式）中经常发生改变。失活具有独特的生物学和行为；然而，目前尚无针对此的靶向治疗方法。肺癌的独特、普遍的分子亚型，而传统上靶向不活跃或不活跃的癌症是具有挑战性的。如果缺乏肿瘤抑制因子，其效应途径可能为治疗提供合理的靶点机会干涉。 LKB1 基因编码调节细胞生长、极性和代谢的丝氨酸/苏氨酸激酶。 LKB1 的重要功能是负向调节三个 CREB 转录共激活因子家族（CRTC1、 2,3)，它们在新陈代谢、衰老和癌症中发挥着至关重要的作用。去磷酸化 CRTC 水平提高，随后易位至细胞核并促进 CREB 依赖性基因在癌细胞中的转录然而，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仍不清楚，例如知识对于发现新的治疗策略至关重要。因此，我们提出的研究目标是。通过阐明 LKB1 失活诱导的信号传导的重要性来弥补这一重大差距根据我们已发表的初步数据，我们追踪了异常的 CRTC。激活是肺部恶性肿瘤中 LKB1 缺失的核心驱动事件，呈现出独特的脆弱性 LKB1 失活肺癌的研究将通过两个具体目标进行检验。 LKB1 失活肺癌中异常激活的 CRTC-CREB 信号传导的功能意义，以及目标 2 将定义 LKB1 失活肺癌中 CRTC-CREB 异常激活的机制。这些拟议研究的成功完成将揭示新的机制和功能见解我们预计 LKB1 失活肺癌的发生和进展中 CRTC 的异常激活。这些努力将验证 CRTC 作为治疗靶点，揭示新的治疗策略，并做出贡献 LKB1 失活有助于我们对癌症生物学的机制理解。