Elucidating the role of support signaling in promoting minimal residual disease in mouse models of oncogene-driven lung cancer

摘要 肺癌是全球癌症相关死亡人数最多的疾病，估计有140万人死于肺癌 全球每年有约16万人死亡，美国每年约有16万人死亡。治疗结果在以下方面有所改善 近年来，随着我们最近的理解，患者可以根据是否存在子集来划分 在他们的肿瘤中发生的特定基因突变。这些致癌基因突变可以作为预测 生物标志物，这些肿瘤可以通过某些特定的治疗方法进行靶向治疗。这种方法已经得到了改进 针对某些癌基因突变患者的治疗选择，但不是大多数患者。最终， 即使对靶向治疗的最好反应也会导致戏剧性的、但短暂的反应。一小块 细胞群体仍然难治并存活下来，构成了众所周知的微小残留病。 (MRD)。MRD提供了导致耐药性的分子基础和根源--这是临床上最紧迫的问题之一 在与癌症的斗争中苦苦挣扎。 在这项提议中，我开始了解WT、EGFR或其他ERBB家族成员在调节 致癌程序、靶向治疗的敏感性以及小鼠和肺器官模型中的MRD 癌症。这个项目中描述的工作将使我能够使用优雅的遗传系统来分离 与ERBB家族其他成员不同，WT EGFR在一些 肺癌最常见的分子亚型。我还将能够定义EGFR损失的后果 使用最先进的单细胞RNA测序技术进行MRD。归根结底，这些项目的长期目标 分析是识别和理解驱动MRD和部署的分子机制 合理的、有针对性的多种治疗策略，以根除恶性肺癌中的MRD。

ABSTRACT Lung cancer is the global leader in cancer related deaths, and responsible for an estimated 1.4 million deaths worldwide and ~160,000 deaths in the United States annually. Treatment outcomes have improved in recent years with our recent understanding that patients can be divided into subsets based on the presence of specific genetic mutations that occur in their tumors. These oncogenic mutations can serve as predictive biomarkers that these tumors can be targeted with certain specific therapeutics. This approach has improved therapeutic options for patient with certain oncogenic mutations, but not the majority of patients. Ultimately, even the best responses to targeted therapeutics result in dramatic, but transient responses. A small population of cells remain refractory and survive, comprising what is known as minimal residual disease (MRD). MRD provides the molecular basis and roots that drive drug resistance - one of the most urgent clinical struggles in the war against cancer. In this proposal I set out to understand the role of WT EGFR or other ERBB family members in modulating oncogenic programs, the sensitivity to targeted therapies, and MRD in mouse and organoid models of lung cancer. The work described in this project will allow me to use elegant genetic systems to separate out the distinct role and contributions for WT EGFR from other ERBB family members in the context of some of the most common molecular subtypes of lung cancer. I will also be able to define the consequences of EGFR loss on MRD using state-of-the-art single cell RNA-sequencing technologies. Ultimately, the long-term goal of these analyses is to identify and understand the molecular mechanisms that drive MRD and the deployment of rational, targeted polytherapy strategies to eradicate MRD in malignant lung cancers.