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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要靶向治疗的最新进展彻底改变了肺癌的临床实践。肺腺癌受体酪氨酸激酶 (RTK) 和 RAS 通路中存在频繁的突变/扩增/融合癌基因，其中许多可以通过 FDA 批准的疗法来靶向。然而，大多数患者确实没有针对性的治疗方案。我们之前的工作发现了肺中的体细胞 RIT1 突变并发现 RIT1 变体作为功能获得性突变来促进细胞转化和耐药性。 RIT1 扩增和过度表达可能发挥类似的致病作用。 RIT1 突变也存在于髓性白血病和努南综合征个体的种系中。在所有疾病中，RIT1 突变与其他 RAS 通路突变是相互排斥的，这意味着 RIT1 RAS 通路驱动基因。然而，我们最近的初步数据表明，RIT1 和 KRAS 有很大不同促进肿瘤发生所需的下游效应器。进一步了解细胞后果 RIT1突变的研究将为治疗RIT1突变癌症开辟新策略。在本提案中，我们定义了 RIT1 突变在肺癌中的作用机制，并测试了两种药物的功效新的治疗策略。以我们的初步研究为基础，这些研究构成了 RIT1 的首次全球分析功能，我们现在将：（1）确定 RIT1-YAP1 在肺癌中协同作用的机制，（2）确定如何 USP9X-RIT1 轴调节纺锤体装配检查点和抗有丝分裂治疗的敏感性，以及 (3) 确定抗 YAP1/TEAD 和抗有丝分裂疗法在 RIT1 突变肺癌中的治疗潜力。最终，这项工作将增进我们对 RIT1 突变在癌症和癌症中的作用和机制的理解。贡献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。我们的访问新颖的源自患者和基因工程的小鼠模型，再加上我们在功能性和功能性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 突变癌症患者的治疗结果。