Understanding and exploiting novel therapeutic vulnerabilities of RIT1-driven lung cancer

项目总结/摘要 靶向治疗的最新进展彻底改变了肺癌的临床实践。肺腺癌 在受体酪氨酸激酶（RTK）和RAS通路中存在频繁突变/扩增/融合 致癌基因，其中许多可以通过FDA批准的治疗靶向。然而，大多数患者 没有针对性的治疗方案。我们以前的工作确定了肺组织中的体细胞RIT 1突变 腺癌，并发现RIT 1变体作为功能获得性突变来促进细胞增殖 转化和耐药性。RIT 1扩增和过表达可能发挥类似的致病作用。 RIT 1突变也发现于髓性白血病和努南综合征个体的生殖系中。 在所有疾病中，RIT 1突变与其他RAS途径突变相互排斥，暗示RIT 1是 RAS途径驱动基因。然而，我们最近的初步数据表明，RIT 1和KRAS有很大的不同， 在下游效应子中需要促进肿瘤发生。进一步了解细胞后果 RIT 1突变的研究将为RIT 1突变型癌症的治疗开辟新的策略。 在这项提案中，我们定义了RIT 1突变在肺癌中的作用机制，并测试了两种治疗方法的疗效。 新的治疗策略。基于我们的初步研究，构成了RIT的第一个全球概况1 功能，我们现在将：（1）确定RIT 1-YAP 1协同作用在肺癌中的机制，（2）确定RIT 1-YAP 1协同作用在肺癌中的作用机制，（3）确定RIT 1-YAP 1协同作用在肺癌中的作用机制，（4）确定RIT 1-YAP 1协同作用在肺癌中的作用机制。 USP 9 X-RIT 1轴调节纺锤体组装检查点和对抗有丝分裂疗法的敏感性，以及（3） 确定抗YAP 1/TEAD和抗有丝分裂疗法在RIT 1突变型肺癌中的治疗潜力。 最终，这项工作将促进我们对RIT 1突变在癌症中的作用和机制的理解， 提供将这些发现转化为新的临床试验所需的理论依据和临床前数据。我们的接入 新型患者衍生和基因工程小鼠模型，再加上我们在功能和生物学方面的专业知识， 基因组学和临床前研究，使我们的实验室非常适合发现新的治疗选择 并改善RIT 1突变型癌症患者的预后。

PROJECT SUMMARY/ABSTRACT Recent advances in targeted therapies have revolutionized lung cancer clinical practice. Lung adenocarcinomas harbor frequent mutations/amplifications/fusions in receptor tyrosine kinase (RTK) and RAS pathway oncogenes, many of which can be targeted by FDA-approved therapies. However, the majority of patients do not have targeted treatment options. Our previous work identified somatic RIT1 mutations in lung adenocarcinomas and discovered that RIT1 variants act as gain-of-function mutations to promote cellular transformation and drug resistance. RIT1 amplification and overexpression may play a similar pathogenic role. RIT1 mutations also are found in myeloid leukemias and in the germline of individuals with Noonan Syndrome. In all diseases, mutations in RIT1 are mutually exclusive with other RAS-pathway mutations, implicating RIT1 as a RAS-pathway driver gene. However, our recent preliminary data show that RIT1 and KRAS substantially differ in the downstream effectors needed to promote tumorigenesis. Further understanding the cellular consequences of RIT1 mutations will open up new strategies for treatment of RIT1-mutant cancers. In this proposal, we define the mechanism of action of RIT1 mutations in lung cancer and test the efficacy of two new treatment strategies. Building on our preliminary studies that constitute the first global profiling of RIT1 function, we now will: (1) Identify the mechanism of RIT1-YAP1 synergy in lung cancer, (2) Determine how a USP9X-RIT1 axis regulates the spindle assembly checkpoint and sensitivity to anti-mitotic therapies, and (3) Define the therapeutic potential of anti-YAP1/TEAD and anti-mitotic therapies in RIT1-mutant lung cancer. Ultimately, this work will advance our understanding of the role and mechanism of RIT1 mutations in cancer and contribute the rationale and pre-clinical data needed to translate these findings into new clinical trials. Our access to novel patient-derived and genetically-engineered mouse models, coupled with our expertise in both functional genomics and pre-clinical studies, make our laboratory uniquely well-suited to discover new therapeutic options and improve outcomes for patients with RIT1-mutant cancers.