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    Joanna Rae Kovalski.
    Characterizing the protein interactome of difficult-to-drug oncogenes, such as Ras, may identify new cancer targets. We undertook live-cell proximity-dependent protein labeling with wild type (WT) and oncogenic mutant (MT) KRAS, NRAS and HRAS isoforms in their associated tumor types, postulating that proximity-dependent protein labeling could detect interactions mediating pro-cancer functions missed by conventional approaches. This identified known, direct Ras interactors, including Raf and PI3K, as well as 130 new Ras-proximal proteins. The interactome was enriched for well-known Ras regulated roles such as cytoskeletal organization, cell junction integrity and cytoplasmic signaling pathways as well as a surprising group of small molecule transport proteins. Moreover, each Ras isoform exhibited a unique set of biological process enrichments, shedding light on isoform specific the functional pathways. A CRISPR genetic screen in 10 cell types demonstrated that 17 of these novel candidates phenocopied oncogenic Ras loss, resulting in decreased proliferation. Combined genetic and proteomic analysis identified well know oncogenic Ras effectors, Raf and PI3K; however, mTOR was the top oncogenic Ras interactor. mTOR-oncogenic Ras interaction is direct and occurs in human mutant KRAS tumors. The interaction depends upon mTORC2 constituents Rictor and MAPKAP1, but not mTORC1 component Raptor. Disruption of the oncogenic Ras-mTORC2 interaction blocked Ras-driven tumorigenesis in vivo via transcriptional regulation of cell cycle progression. Proximity-dependent protein labeling and CRISPR genetics thus synergize to identify new targets in cancers driven by Ras and other dominant oncogenes.
    Digital Access   2017