YAP1 and RB1 cooperate to regulate lung cancer lineage plasticity and therapeutic resistance

项目总结 本申请是为了回应被确认为非CA-CA的特殊利益通知(NOSI)而提交的 23-045.EGFR突变肺腺癌(LUAD)患者应用EGFR酪氨酸激酶治疗 抑制剂(TKI)，因为与以前的护理标准相比，它们产生了更好的患者结果。EGFR TKI不是 然而，由于几乎所有患者由于获得性耐药性而在治疗上取得进展，因此是治愈的。虽然遗传 获得性EGFR TKI耐药的机制是众所周知的，非遗传机制也发挥着作用 重要的角色。涉及谱系状态变化的动态和可逆转录适应支持 LUAD细胞在治疗过程中的存活和进展。基因控制的机制和决定因素 这种LUAD的谱系可塑性还没有被很好地理解。推进对LUAD谱系的基本认识 可塑性是发展预测、抑制和改善可塑性的治疗方法的先决条件。 治疗效果。通过对临床标本和实验模型的分析，合作 研究人员发现，在EGFR TKI中存活的微小残留病显示出诱导静止的， 肺泡谱系状态。这种状态在通过EGFR TKI增殖和进展的细胞中消失，并被取代 通过替代血统状态，减少对致癌EGFR信号的依赖。在目前平行的研究领域 在合作研究人员的实验室中，YAP1的活性已经被证明可以驱动肺泡谱系 而RB1基因的缺失加速了向EGFR独立的替代世系状态的进一步过渡。这些 研究结果表明，在EGFR TKI治疗期间，YAP1和RB1相互作用控制谱系状态转换 最终促进获得性治疗抵抗。此Artnet补充应用程序旨在 支持两个特定目标的合作研究，这两个目标将检验这一假说并从基因上验证新的 用于研究LUAD体内谱系可塑性的工程化小鼠模型，另外还使研究如何 肿瘤微环境中的非恶性细胞影响LUAD谱系可塑性，反之亦然。

PROJECT SUMMARY This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-045. Patients with EGFR mutant lung adenocarcinoma (LUAD) are treated with EGFR tyrosine kinase inhibitors (TKI) because they yield better patient outcomes than previous standards of care. EGFR TKI are not curative, however, as virtually all patients progress on therapy due to acquired drug resistance. While genetic mechanisms of acquired EGFR TKI resistance are well understood, non-genetic mechanisms also play an important role. Dynamic and reversible transcriptional adaptations involving lineage state changes support the survival and progression of LUAD cells during treatment. The mechanisms and genetic determinants controlling this LUAD lineage plasticity are not well understood. Advancing fundamental understanding of LUAD lineage plasticity is a prerequisite for the development of therapeutic approaches to predict it, suppress it, and improve therapeutic outcomes. Through analysis of both clinical specimens and experimental models, the collaborating investigators have discovered that minimal residual disease surviving EGFR TKI shows induction of a quiescent, alveolar lineage state. This state is lost in cells proliferating and progressing through EGFR TKI and is replaced by alternative lineage states less dependent on oncogenic EGFR signaling. In currently parallel lines of research within the collaborating investigators labs, YAP1 activity has been demonstrated to drive the alveolar lineage state while RB1 loss accelerates the further transition to alternative, EGFR independent lineage states. These findings suggest YAP1 and RB1 interact to control lineage state transitions during EGFR TKI therapy that ultimately facilitate acquired therapeutic resistance. This ARTNET supplement application is proposed to support collaborative research in two specific aims that will test this hypothesis and validate new genetically engineered mouse models for studying LUAD lineage plasticity in vivo, additionally enabling the study of how non-malignant cells within the tumor microenvironment influence LUAD lineage plasticity and vice versa.