Project 3

项目总结 基因定向治疗是治疗相当大比例的晚期非霍奇金淋巴瘤的标准疗法。 小细胞肺癌患者，其肿瘤在EGFR内存在靶向基因突变， ALK、ROS1、BRAF、RET、MET、NTRK或HER2。虽然这种治疗方法是有效的， 获得性耐药性不可避免地会发生。收购的当前管理战略 耐药是通过活检来评估耐药的机制，以帮助指导后续 治疗。然而，耐药机制可以是异质性的，并不是所有患者的肿瘤都是如此。 建立一个可行的抵抗机制。此外，即使一个有针对性的机制 耐药性被确定，随后的治疗方法可用，获得性耐药性将会发展。 再来一次。另一种策略是在临床发展之前进行治疗干预 通过特定靶向残留耐药持久性(DTP)细胞获得耐药性， 在有效的基因导向治疗后保留下来的一小部分细胞，最终 会引起后天的抵抗力。目前还没有针对DTP的临床策略， 部分原因是缺乏对这种状态的生物学和机械性理解。 在这个项目中，我们将通过以下方式为针对DTP细胞的临床治疗策略奠定基础 发现导致DTP状态形成的因素，并确定可以杀死DTP的目标 细胞。我们将以我们团队围绕EGFR中DTP状态的先前研究为基础- 突变型肺癌显示：1)YAP/TEAD激活导致转录抑制 促凋亡蛋白BMF从而限制EGFR抑制剂介导的细胞凋亡；2)DTP状态 显示细胞衰老的一些特征和抗凋亡药物可能是一种有效的 策略；以及3)肿瘤微环境中的肿瘤相关成纤维细胞可以促进DTP 出现并调节已建立的DTP的衰老表型。以此为基础 基金会，本项目中详细介绍的实验利用了创新技术的组合 以及一组独特的、大量的患者来源的癌症和成纤维细胞模型 基因驱动的癌症了解DTP状态的脆弱性并进行优化设计 对抗这些患者耐药先兆的临床方法。

PROJECT SUMMARY Genotype directed therapy is the standard of care for the significant proportion of advanced non- small cell lung cancer patients whose tumors harbor a targetable genetic mutation within EGFR, ALK, ROS1, BRAF, RET, MET, NTRK or HER2. Although this therapeutic approach is effective, acquired drug resistance inevitably occurs. The current management strategy for acquired resistance is to evaluate the mechanism of resistance with a biopsy to help guide subsequent treatment. However, mechanisms of resistance can be heterogenous and not all patients’ tumors harbor an actionable resistance mechanism. Moreover, even when a targetable mechanism of resistance is identified and a subsequent therapy available, acquired resistance will develop again. An alternative strategy is to intervene therapeutically prior to the clinical development of acquired drug resistance by specifically targeting the residual drug tolerant persister (DTP) cells, a small population of cells that remain after effective genotype directed therapies and ultimately give rise to acquired resistance. There have been no clinical strategies developed against DTPs, in part due to the lack of the biological and mechanistic understanding of this state. In this project we will lay the foundation for clinical therapeutic strategies aimed at DTP cells by uncovering factors that lead to formation of the DTP state and identifying targets that can kill DTP cells. We will build on prior research from our group centered around the DTP state in EGFR- mutant lung cancer showing: 1) YAP/TEAD activation results in transcriptional repression of the pro-apoptotic protein BMF and thus limits EGFR inhibitor mediated apoptosis; 2) the DTP state displays some features of cellular senescence and anti-apoptosis agents may be an effective strategy; and 3) cancer-associated fibroblasts in the tumor microenvironment can facilitate DTP emergence and modulate the senescence phenotype of established DTPs. Building upon this foundation, the experiments detailed in this project utilize a combination of innovative techniques and a unique and large collection of patient-derived cancer and fibroblast models from genomically-driven cancers to understand the vulnerabilities of the DTP state and design optimal clinical approaches to combat these harbingers of drug resistance in patients.