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

了解和利用 RIT1 驱动的肺癌的新治疗漏洞

• 批准号: 10641671
• 负责人: Alice Berger
• 金额: $ 45.8万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641671
• 关键词: Antimitotic Agents; BRAF gene; Biochemical; Biological; CRISPR screen; Cancer cell line; Cells; Chromosomal Rearrangement; Clinical Trials; Complex; Coupled; Data; Development; Disease; Drug Screening; Drug resistance; Epidermal Growth Factor Receptor; Epithelial Cells; Event; FDA approved; Family; Genes; Genetic; Genetically Engineered Mouse; Genomics; Genotype; Goals; Human; Impairment; Individual; KRAS2 gene; Laboratories; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mediating; Mitotic Checkpoint; Molecular; Monomeric GTP-Binding Proteins; Mutate; Mutation; Myeloid Leukemia; Nature; Noonan Syndrome; Oncogenes; Oncogenic; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Play; Postdoctoral Fellow; Precision therapeutics; Proteins; Proteomics; Receptor Protein-Tyrosine Kinases; Regulation; Resistance; Role; Signal Transduction; Structure; Survival Rate; Testing; The Cancer Genome Atlas; Therapeutic; Translating; Translations; United States; Variant; Work; aurora kinase; aurora kinase A; cancer cell; cancer subtypes; cancer therapy; clinical practice; driver mutation; efficacy testing; experimental study; functional genomics; gain of function mutation; genome-wide; improved; improved outcome; inhibitor; insight; kinase inhibitor; lung cancer cell; lung tumorigenesis; metaplastic cell transformation; mutant; novel; novel therapeutic intervention; novel therapeutics; overexpression; patient derived xenograft model; pre-clinical; precision oncology; preclinical study; protein complex; ras Proteins; small molecule; synergism; targeted treatment; translational potential; treatment strategy; tumor; tumorigenesis; tumorigenic

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.

项目摘要/摘要 靶向疗法的最新进展彻底改变了肺癌临床实践。肺腺癌 受体酪氨酸激酶（RTK）和RAS途径的港口频繁突变/扩增/融合 癌基因，其中许多可以由FDA批准的疗法靶向。但是，大多数患者这样做 没有目标治疗方案。我们以前的工作确定了肺中的体细胞RIT1突变 腺癌，发现RIT1变体起到功能增益突变来促进细胞 转化和耐药性。 RIT1扩增和过表达可能起着相似的致病作用。 RIT1突变也存在于髓样白血病和Noonan综合征个体的种系中。 在所有疾病中，RIT1中的突变与其他RAS-Pathway突变相互排斥，将RIT1视为 RAS-Pathway驱动器基因。但是，我们最近的初步数据表明RIT1和KRAS有很大差异 在促进肿瘤发生所需的下游效应子中。进一步了解细胞后果 RIT1突变将开辟新的策略来治疗RIT1突变癌。 在此提案中，我们定义了RIT1突变在肺癌中的作用机理，并测试了两个 新的治疗策略。以我们的初步研究为基础，构成RIT1的首次全球分析 功能，我们现在将：（1）确定肺癌中RIT1-YAP1协同作用的机理，（2）确定A USP9X-RIT1轴调节纺锤体组件检查点和对抗脱粒质疗法的敏感性，（3） 定义RIT1突变肺癌中抗-YAP1/TEAD和抗丝分裂疗法的治疗潜力。 最终，这项工作将促进我们对RIT1突变在癌症和 将这些发现转化为新的临床试验所需的基本原理和临床前数据。我们的访问 为新颖的患者来源和遗传工程的小鼠模型，再加上我们在两个功能方面的专业知识 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RIT1突变癌患者的预后。