RNAi has become a powerful genetic tool for dissecting genetic dependencies in cancer cells. Current generation of siRNA libraries are not knockdown validated and therefore do not provide full saturation of the genome. PURPOSE. In this project we aim to accomplish the following goals: 1) constructing a high quality siRNA library targeting Ras family and related genes in which individual siRNAs is knockdown validated;2) use this siRNA library to screen a panel of human cancer cell lines with or without KRAS mutations to identify those siRNAs that show synthetic lethality among the KRAS mutant cell lines;and 3) functional dissection of the mechanisms of candidate synthetic lethal genes using molecular and pharmacological tools. SIGNIFICANT MATERIALS AND METHODS. Knockdown validated siRNA library targeting Ras Ras pathway genes. FY2013 ACCOMPLISHMENT. We have screened a large number of siRNAs against Ras pathway genes and identified those that gave potent knockdown. We have demonstrated that potent siRNAs can be combined to target multiple genes and in collaboration we showed that these siRNAs can be delivered in vivo to target undruggable targets including KRAS. A manuscript has been submitted for publication.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011437-02
Application #
8763524
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2013
Total Cost
$176,241
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
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State
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