The HDAC3 pathway in LKB1-mutant lung cancer and senescence

项目摘要/摘要 STK11/LKB1抑癌基因在约15%的非小细胞肺癌中发生突变 病例，使其成为第三种最常见的基因改变。LKB1经常与Kras共突变，并且 LKB1突变的肿瘤生物学因其独特性而日益受到癌症领域的关注 对潜在肿瘤生物学的研究，加上缺乏有针对性的治疗选择，正受到越来越多的关注。 最近的工作发现，在Kras驱动的非小细胞肺癌中，HDAC3复合体具有强大的促肿瘤功能， 并发现HDAC3与肺癌谱系转录因子NKX2-1合作，驱动一种 具有LKB1突变的肺癌细胞中独特的转录程序。有趣的是，不管LKB1 突变状态，HDAC3也被发现直接抑制衰老相关的分泌 表型(SASP)，通过p65核因子-kB。本提案中概述的工作旨在(1)阐明 对观察到的LKB1突变肿瘤特有的转录脆弱性的机械解释， 以及(2)确定HDAC3蛋白复合体如何调节SASP和免疫细胞招募以 影响肺癌生长控制。实验将确定HDAC3和NKX2-1的基因组结合 LKB1突变细胞特有的模式和相互作用伙伴，IIa类HDAC是否有助于 LKB1突变株中HDAC3功能的LKB1特异性及其对HDAC3抑制的治疗反应 肿瘤。这些研究还将定义HDAC3如何影响p65基因组结合和活性，确定哪些 核受体是HDAC3抑制SASP所必需的，并描述了HDAC3依赖的 瘤内免疫渗透及其在体内生长控制中的作用。从这项工作中获得的见解 将有助于理解关键的LKB1特异转录途径以及它们可能是如何 在治疗上受到冲击。本研究还旨在明确HDAC3的调节机制 控制SASP，这将有助于探索SASP参与肿瘤的关键问题 更广泛的增长控制。应聘者拥有生物化学博士学位，目前正在完成学业。 在索尔克生物研究所与鲁本·肖博士一起进行博士后培训。候选人的 职业目标是获得一个研究癌症转录放松管制的终身教职。 这些研究将为在这一重要的新兴领域继续开展研究计划奠定基础 癌症研究领域。

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.