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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：
Shyam Biswal
金额：
$ 40.34万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
https://reporter.nih.gov/project-details/9897626
关键词：
5&apos -AMP-activated protein kinase Adenocarcinoma Adenocarcinoma Cell Affect Animals Antioxidants Automobile Driving Cell Line Cell Proliferation Cell Survival Cells Collaborations Data Defect Drug Metabolic Detoxication Gene Mutation Gene Silencing Genetic Genetically Engineered Mouse Growth Histologic Homeostasis Human Impairment In Vitro Knock-out Knowledge Lead Lung Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Metabolic Metabolic Pathway Metabolic stress Modeling Molecular Mus Mutate Mutation NADP Non-Small-Cell Lung Carcinoma Nutrient Oncogenic Oxidation-Reduction Pathway interactions Proteins Reaction Reactive Oxygen Species Resistance Role STK11 gene Signal Transduction Stress The Cancer Genome Atlas Transgenic Mice Up-Regulation cell growth energy balance expectation improved in vivo inhibitor/antagonist loss of function mutation lung tumorigenesis metabolomics mortality mouse model mutant neoplastic cell new therapeutic target novel pre-clinical public health relevance response small molecule stable isotope transcriptomics tumor tumor 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.