权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
Lizi Wu
金额：
$ 33.54万
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 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10558734
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 Metabolism Molecular Mutation Non-Small-Cell Lung Carcinoma Pathway interactions Peptides Phosphorylation Protein Dephosphorylation Protein-Serine-Threonine Kinases Proteins Proteomics Publishing Research Role STK11 gene Serine Signal Induction 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 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.

项目总结/文摘