Wang, Belinda2018-05-182018-052018-05-152018Wang, Belinda. 2018. Synthetic Lethal Interactions With Oncogenic KRAS. Doctoral dissertation, Harvard Medical School.http://nrs.harvard.edu/urn-3:HUL.InstRepos:37006458KRAS is one of the most frequently mutated genes across human cancers, including 96% of pancreatic cancers, 40% of colorectal cancers, and 35% of lung cancers. The majority of human cancer cell lines and tumors from genetically engineered mouse models harboring an oncogenic mutant KRAS allele demonstrate a strong dependence on KRAS for proliferation and survival. This KRAS dependency is a type of ‘oncogene addiction,’ a state in which cancer cells depend on signaling from a single oncogene for survival. Unfortunately, the development of clinically effective KRAS-directed cancer therapies has been unsuccessful, and KRAS-mutant cancers are refractory to standard and targeted therapies. Alternative approaches to combatting KRAS-mutant cancers are clearly needed. We postulate that oncogenic KRAS signaling induces changes in cell signaling networks that cause cells to become dependent on certain genes, termed a ‘synthetic lethal’ interaction. Identifying these selective vulnerabilities would lend insight to the pathways altered in KRAS-mutant cancers and may inform novel strategies to target KRAS-addicted cancers. In this thesis, we systematically identify candidate co-dependencies of oncogenic KRAS by analyzing genetic dependencies revealed by genome-scale RNAi screens across a large panel of cell lines. We highlight methods to facilitate candidate selection/validation and integrate analyses of gene-expression data and genome-scale CRISPR/Cas9 screens to nominate candidate co-dependencies for further study. In addition, we examine CRISPR-Cas9 screens to identify genes that modify sensitivity to small molecule MAPK pathway inhibition (MAPKi) in RAS-mutant cancers. We propose that suppression of the DOCK5-RAC1 pathway demonstrates a drug-conditional lethal interaction with small molecule MAPK pathway inhibitors in RAS-mutant cancers. We believe that these data provide a foundation for further examination of genetic co-dependencies of oncogenic KRAS and the potential synthetic lethal interaction between DOCK5-RAC1 pathway suppression and MAPKi in RAS mutant cancers.application/pdfenThesis or Dissertation2018-05-18