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A multi-faceted approach to identifying K-Ras synthetic lethal relationships

识别 K-Ras 合成致死关系的多方面方法

基本信息

批准号：
10224565
负责人：
STEPHEN J ELLEDGE
金额：
$ 15万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-25 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224565
关键词：
multi faceted approach identifying Ras

项目摘要

DESCRIPTION (provided by applicant): More than 200,000 Americans die as a result of lung and colorectal cancer each year. Decreasing the frequency of deaths due to these cancers will undoubtedly require tailoring an individual's treatment to the specific mutations that have occurred in their cancer. Activating mutations in the K-Ras oncoprotein are common in lung and colorectal cancers and are associated with particularly poor response to both conventional and targeted therapies. Our overarching goal is to understand the mechanisms underlying the oncogenic properties of mutant K-Ras in order to develop targeted therapeutic strategies. This project includes three phases. In the first phase of our project, we will use CRISPR technology to generate K-Ras wild-type derivatives of lung and colorectal cancer cells expressing endogenous mutant K-Ras. We will then comprehensively characterize the cellular and molecular phenotypes associated with loss of mutant K-Ras, for example by combining multiplexed mass spectrometry with computational modeling to identify the signal transduction network utilized by mutant K-Ras to transform cells. This study will also include an analysis of radiation response in wild-type and mutant cells, as activated K-Ras is known to confer resistance to ionizing radiation. In the second phase of our project, we will perform a variety of genome-wide and targeted screens for genes that when knocked down or over-expressed cause lethality in the context of mutant KRas in vitro and in vivo. These studies will utilize stat-of-the-art high-throughput screening technologies, including doxycycline-inducible shRNAs and open reading frames, that we have perfected over the past decade. In the final phase of the project, we will identify K-Ras synthetic lethals that are therapeutically targetable and then perform preclinical studies in genetically engineered mouse models of lung and colon cancer. The utilization of genetically controlled mouse and human experimental systems will allow us to identify gene products that are truly selectively required in cancer cells expressing mutant K-Ras. In the end, this work will have a major impact for patients who develop K-Ras mutant cancer.

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

KRAS Alleles: The Devil Is in the Detail.

DOI：
10.1016/j.trecan.2017.08.006
发表时间：
2017-10
期刊：
Trends in cancer
影响因子：
18.4
作者：
Haigis KM
通讯作者：
Haigis KM

A Role for Mitochondrial Translation in Promotion of Viability in K-Ras Mutant Cells.

DOI：
10.1016/j.celrep.2017.06.061
发表时间：
2017-07-11
期刊：
Cell reports
影响因子：
8.8
作者：
Martin TD;Cook DR;Choi MY;Li MZ;Haigis KM;Elledge SJ
通讯作者：
Elledge SJ

Functional genomics reveals that tumors with activating phosphoinositide 3-kinase mutations are dependent on accelerated protein turnover.

DOI：
10.1101/gad.290122.116
发表时间：
2016-12-15
期刊：
Genes & development
影响因子：
10.5
作者：
Davoli T;Mengwasser KE;Duan J;Chen T;Christensen C;Wooten EC;Anselmo AN;Li MZ;Wong KK;Kahle KT;Elledge SJ
通讯作者：
Elledge SJ

No back seat for a progression event-K-RAS as a therapeutic target in CRC.