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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.

项目总结/文摘