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

Kevin Michael Haigis

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National Institutes of Health (NIH)
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.

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