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Principal Investigator: Alice Berger
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $129,789
Funding agency: National Cancer Institute
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.
Terms: <AIK gene><ARK1><AURKA><AURORA2><Aik protein><Antimitotic Agents><Antimitotic Drugs><Antimitotics><Aurora-Related Kinase 1><Aurora/IPL1-Like Kinase><B-raf-1><BRAF><BRAF gene><BTAK><Biochemical><Biological><C-K-RAS><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Cancer Genes><Cancer Treatment><Cancer cell line><Cancer-Promoting Gene><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Transformation><Chromosomal Rearrangement><Clinical Trials><Complex><Coupled><Data><Development><Disease><Disorder><Drug Screening><Drug resistance><EGF Receptor><EGFR><ERBB Protein><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Epithelial Cells><Event><FDA approved><Family><GEM model><GEMM model><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetically Engineered Mouse><Genomics><Genotype><Germ Lines><Goals><Granulocytic Leukemia><HER1><Human><Impairment><Individual><Intracellular Communication and Signaling><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Laboratories><Lung><Lung Adenocarcinoma><Lung Neoplasms><Lung Respiratory System><Lung Tumor><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Maps><Mediating><Microtubular Function Inhibitors><Mitosis Checkpoint><Mitosis Inhibitor Agents><Mitosis Inhibitor Drugs><Mitosis Inhibitors><Mitotic Checkpoint><Mitotic Inhibitor Agents><Mitotic Inhibitor Drugs><Mitotic Inhibitors><Modern Man><Molecular><Monomeric G-Proteins><Monomeric GTP-Binding Proteins><Mutate><Mutation><Myelocytic Leukemia><Myelogenous Leukemia><Myeloid Leukemia><Nature><Non-Lymphoblastic Leukemia><Non-Lymphocytic Leukemia><Nonlymphoblastic Leukemia><Nonlymphocytic Leukemia><Noonan Syndrome><Oncogene K-Ras><Oncogenes><Oncogenesis><Oncogenic><PDX model><PTK Receptors><Pathogenicity><Pathway interactions><Patient derived xenograft><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pattern><Play><Postdoc><Postdoctoral Fellow><Precision therapeutics><Proteins><Proteomics><Pulmonary Cancer><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><RAFB1><RASK2><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Regulation><Research Associate><Resistance><Role><STK15><STK6><STK6 gene><STK6, Mouse, Homolog of><Serine/Threonine Protein Kinase 15><Signal Transduction><Signal Transduction Systems><Signaling><Small G-Proteins><Small GTPases><Structure><Survival Rate><TCGA><TGF-alpha Receptor><Testing><The Cancer Genome Atlas><Therapeutic><Transforming Genes><Transforming Growth Factor alpha Receptor><Translating><Translations><Transmembrane Receptor Protein Tyrosine Kinase><Turner phenotype with normal karyotype><Turner syndrome in female with X chromosome><Turner-like syndrome><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Ullrich-Noonan syndrome><United States><Urogastrone Receptor><Variant><Variation><Work><anti-cancer therapy><aurora kinas><aurora kinase><aurora kinase A><aurora-kinase A><biologic><biological signal transduction><c-erbB-1><c-erbB-1 Protein><cancer cell><cancer sub-types><cancer subtypes><cancer therapy><cancer-directed therapy><clinical practice><clustered regularly interspaced short palindromic repeats screen><developmental><driver lesion><driver mutation><drug resistant><efficacy testing><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><experiment><experimental research><experimental study><experiments><familial Turner syndrome><functional genomics><gain of function mutation><genetically engineered mouse model><genetically engineered murine model><genome mutation><genome scale><genome-wide><genomewide><improved><improved outcome><individualized cancer care><individualized oncology><inhibitor><insight><kinase inhibitor><lung cancer><lung cancer cell><lung tumorigenesis><malignancy><metaplastic cell transformation><mitosis check point><mitotic check point><mutant><myeloid granulocytic leukemia><myelosis><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><overexpress><overexpression><pathway><patient derived xenograft model><patient oriented outcomes><personalized oncology><post-doc><post-doctoral><post-doctoral trainee><pre-clinical><pre-clinical study><precision cancer care><precision cancer medicine><precision oncology><precision therapies><precision treatment><preclinical><preclinical study><protein complex><proto-oncogene protein c-erbB-1><pseudo-Ullrich-Turner syndrome><pulmonary><ras Gene Products><ras Proteins><research associates><resistance to Drug><resistant><resistant to Drug><small molecule><social role><synergism><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><translation><translational opportunities><translational potential><treatment strategy><tumor><tumorigenesis><tumorigenesis in the lung><tumorigenic><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><v-raf Murine Sarcoma Viral Oncogene Homolog B1>