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

• DOI: 10.1016/j.celrep.2017.06.061
• Publication Date: 2017-07-11T18:31:53Z
• Authors: Timothy D. Martin; Danielle R. Cook; Mei Yuk Choi; Mamie Z. Li; Kevin M. Haigis; Stephen J. Elledge
• Keywords: Synthetic Lethality

Activating mutations in the KRAS oncogene are highly prevalent tumors, especially those of colon, lung, and pancreas. To better understand genetic dependencies that K-Ras mutant cells rely upon for their growth, we employed whole-genome CRISPR loss-of-function screens two isogenic pairs cell lines. Since loss essential genes is uniformly toxic CRISPR-based screens, also developed a small hairpin RNA (shRNA) library targeting genes. These approaches uncovered large set proteins whose results selective reduction growth. Pathway analysis revealed many these function mitochondria. For validation, generated lines using genome engineering, which confirmed dependency on mitochondrial pathways. Finally, found inhibitors reduce growth tumors vivo, aiding advancement strategies to target K-Ras-driven malignancy.