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

项目摘要/摘要 靶向治疗的最新进展使肺癌的临床实践发生了革命性的变化。肺腺癌 受体酪氨酸激酶(RTK)和RAS通路的频繁突变/扩增/融合 致癌基因，其中许多可以作为FDA批准的治疗的靶点。然而，大多数患者都这样做 没有针对性的治疗选择。我们先前的工作在肺中发现了体细胞RIT1突变 发现RIT1变异体作为功能获得突变促进细胞 转化和抗药性。RIT1的扩增和过度表达可能起到类似的致病作用。 在髓系白血病和Noonan综合征患者的种系中也发现了RIT1突变。 在所有疾病中，RIT1的突变与其他RAS途径的突变是互斥的，这意味着RIT1 AS RAS途径驱动基因。然而，我们最近的初步数据显示，RIT1和KRAS有很大的不同 在促进肿瘤发生所需的下游效应物中。进一步了解细胞的后果 RIT1突变的研究将为RIT1突变癌症的治疗开辟新的策略。 在这个方案中，我们定义了RIT1突变在肺癌中的作用机制，并测试了两种方法的疗效 新的治疗策略。以我们的初步研究为基础，这些研究构成了RIT1的第一个全球概况 我们现在将：(1)确定RIT1-YAP1在肺癌中协同作用的机制；(2)确定RIT1-YAP1如何在肺癌中发挥协同作用 USP9X-RIT1轴调节纺锤体组装检查点和对抗有丝分裂治疗的敏感性，以及(3) 明确抗YAP1/TEAD和抗有丝分裂疗法在RIT1突变肺癌中的治疗潜力。 最终，这项工作将促进我们对RIT1突变在癌症和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基础和临床前数据。我们的访问权限 到新的患者衍生和基因工程小鼠模型，再加上我们在功能上的专业知识 基因组学和临床前研究使我们的实验室独一无二地非常适合发现新的治疗方案 并改善RIT1突变癌症患者的预后。

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.