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Mechanisms of Pip4k2c and Pip5k1b dependencies in Ras driven squamous cell carcinoma

Ras 驱动的鳞状细胞癌中 Pip4k2c 和 Pip5k1b 依赖性的机制

基本信息

批准号：
10667117
负责人：
CHRISTOPHER J KEMP
金额：
$ 17.6万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667117
关键词：
Affect Apoptosis Attention Binding Biological Assay Carcinogens Cell Cycle Cell Death Cell Line Cell Proliferation Cells Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Credentialing DNA Sequence Alteration Data Dependence Diglycerides Drug Targeting FRAP1 gene Family GTP Binding Gene Expression Genes Genetic Genetic Transcription Genomics Head and Neck Squamous Cell Carcinoma Human Inbred Mouse Inositol KRAS2 gene MEKs Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of urinary bladder Mediator Mitogen-Activated Protein Kinases Molecular Monomeric GTP-Binding Proteins Mus Mutate Mutation Oncogenic Organoids Outcome Pathway interactions Patients Phenotype Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phospholipase C Phosphotransferases Pre-Clinical Model Process RAS genes RAS inhibition RNA Interference Second Messenger Systems Series Signal Pathway Signal Transduction Small Interfering RNA Squamous cell carcinoma TP53 gene Testing The Cancer Genome Atlas Therapeutic Validation Wild Type Mouse cancer cell cancer survival drug candidate drug development experience inhibitor inositol 4,5-bisphosphate interest knock-down knockout gene member mutant mutational status new therapeutic target novel phosphatidylinositol 4-phosphate phosphatidylinositol 5-phosphate protein expression public database ras Oncogene screening small molecule inhibitor targeted agent targeted treatment tripolyphosphate tumor

项目摘要

PROJECT SUMMARY/ABSTRACT The RAS oncogene is mutated in ~19% of all human cancers. However, targeted therapies specific to tumors with RAS mutations are lacking. To identify novel druggable targets to cancers with mutations in Ras we performed arrayed, kinome focused siRNA phenotypic screening utilizing a set of syngeneic Ras mutant squamous cell carcinoma (SCC) cell lines. Out of 571 kinases tested, Pip4k2c and Pip5k1b were top scoring, ranked 18th and 21st respectively and further, Pip4k2c both showed greater dependency in Ras mutant vs. Ras wild type SCC cells. Pip4k2c and Pik5k1b both generate phosphatidyl inositol 4,5-bisphosphate (PIP2) the substrate for Pik3ca (PI3K) and precursor to phosphatidyl inositol 3,4,5-triphosphate (PIP3), a key mediator of oncogenic Ras signaling. While most drug development attention has focused on PI3K, lack of clinical activity associated with PI3K inhibitors has generated renewed interest in targeting other phosphoinositol kinases. Here we propose to credential Pip4k2c and Pip5k1b as a novel dependencies in both mouse and human Ras mutant SCC cells, will establish the basic outline of its prosurvival function, and will identify key cellular and genetic modifiers of this dependency.

项目总结/文摘