The HDAC3 pathway in LKB1-mutant lung cancer and senescence

LKB1突变型肺癌和衰老中的HDAC3通路

• 批准号: 10371465
• 负责人: Lillian J. Eichner
• 金额: $ 19.11万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371465
• 关键词: Acetylation; Area; Attention; Basal Cell; Binding; Biochemistry; Biological; Biology; Cell Aging; Cells; Cessation of life; Complex; Coupled; Disease; Doctor of Philosophy; Faculty; Foundations; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Growth; HDAC3 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Immune; In Vitro; Investigation; Link; Lung; Lung Neoplasms; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Molecular; Mutate; Mutation; NCOR1 gene; NF-kappa B; Non-Small-Cell Lung Carcinoma; Nuclear Receptors; Outcome Study; Pathway interactions; Pattern; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Play; Positioning Attribute; Regulation; Repression; Research; Resistance; Role; STK11 gene; Signal Pathway; Signal Transduction; Source; Specificity; TP53 gene; Therapeutic; Tumor Biology; Tumor Promotion; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; United States; Work; anticancer research; cancer cell; career; experimental study; in vivo; inhibitor; insight; interest; lung cancer cell; lung tumorigenesis; mutant; mutational status; neoplastic cell; novel; p65; pharmacologic; post-doctoral training; pre-clinical; programs; protein complex; recruit; senescence; targeted treatment; tenure track; therapeutic evaluation; transcription factor; treatment response; tumor; tumor growth

Project Summary/Abstract The STK11/LKB1 tumor suppressor is mutated in ~15% of Non-Small Cell Lung Cancer (NSCLC) cases, making it the third most frequent genetic alteration. LKB1 is frequently co-mutated with Kras, and LKB1-mutant tumor biology is becoming increasingly of interest to the cancer field as the uniqueness of the underlying tumor biology coupled with the lack of targeted therapy options is gaining attention. Recent work identified a potent tumor promoting function of the HDAC3 complex in Kras-driven NSCLC, and revealed that HDAC3 cooperates with the lung cancer lineage transcription factor NKX2-1 to drive a unique transcriptional program in lung cancer cells with LKB1 mutation. Interestingly, regardless of LKB1 mutational status, HDAC3 was also found to directly repress the Senescence-Associated Secretory Phenotype (SASP) via p65 NF-kB. The work outlined in this proposal aims to (1) elucidate the mechanistic explanations for the observed transcriptional vulnerabilities unique to LKB1 mutant tumors, and to (2) define how the HDAC3 protein complex regulates the SASP and immune cell recruitment to impact lung tumor growth control. Experiments will determine HDAC3 and NKX2-1 genomic binding patterns and interacting partners specific to LKB1-mutant cells, whether Class IIa HDACs contribute to the LKB1 specificity of HDAC3 function, and therapeutic response to HDAC3 inhibition in LKB1-mutant tumors. These studies will also define how HDAC3 impacts p65 genome binding and activity, identify which Nuclear Receptors are required for HDAC3 repression of the SASP, and profile the HDAC3-dependent intratumoral immune infiltrate and its contribution to growth control in vivo. Insights gained from this work will contribute to the understanding of key LKB1-specific transcriptional pathways and how they may be impinged upon therapeutically. This research also aims to define the mechanism mediating HDAC3 control of the SASP, which will facilitate exploration of key questions about SASP involvement in tumor growth control more broadly. The candidate holds a Ph.D. in Biochemistry and is currently completing her post-doctoral training with Dr. Reuben Shaw at the Salk Institute for Biological Studies. The candidate’s career goal is to obtain a tenure-track faculty position studying transcriptional deregulation in cancer. These studies will provide the foundation for a continued research program in this important, emerging area of cancer research.

项目摘要/摘要 在约15％的非小细胞肺癌（NSCLC）中，STK11/LKB1肿瘤抑制剂突变 案例，使其成为第三次最常见的遗传改变。 LKB1经常与KRAS共同突破，并且 随着癌症的独特性 在潜在的肿瘤生物学以及缺乏靶向治疗方案的情况下，人们引起了人们的关注。 最近的工作确定了KRAS驱动的NSCLC中HDAC3复合物的有效肿瘤促进功能， 并发现HDAC3与肺癌谱系转录因子NKX2-1合作以驱动A 具有LKB1突变的肺癌细胞中的独特转录程序。有趣的是，不管LKB1如何 突变状态，还发现HDAC3直接反映了与衰老相关的分泌 表型（SASP）通过p65 NF-KB。该提案中概述的工作旨在（1）阐明 LKB1突变肿瘤所特有的转录脆弱性的机械解释， 并（2）定义HDAC3蛋白复合物如何调节SASP和IMMUNOCELL募集到 影响肺部肿瘤生长控制。实验将确定HDAC3和NKX2-1基因组结合 模式和相互作用的伴侣特定于LKB1突变细胞，IIA类HDAC是否有助于 HDAC3函数的LKB1特异性以及对LKB1突变物中HDAC3抑制的热响应 肿瘤。这些研究还将定义HDAC3如何影响p65基因组结合和活性，确定哪个 SASP的HDAC3表达需要核受体，并介绍了HDAC3依赖性的 肿瘤内免疫浸润及其对体内生长控制的贡献。从这项工作中获得的见解 将有助于理解关键LKB1特异性转录途径及其可能如何 治疗障碍。这项研究还旨在定义介导HDAC3的机制 控制SASP，这将有助于探索有关SASP参与肿瘤的关键问题 增长控制更广泛。候选人拥有博士学位。在生物化学领域，目前正在完成她 Salk生物学研究所的Reuben Shaw博士的博士后培训。候选人的 职业目标是获得研究癌症转录放松管制的终身教师职位。 这些研究将为持续的研究计划奠定基础 癌症研究领域。