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

Activating mutations in the KRAS oncogene are highly prevalent in tumors, especially those of the colon, lung, and pancreas. To better understand the genetic dependencies that K-Ras mutant cells rely upon for their growth, we employed whole-genome CRISPR loss-of-function screens in two isogenic pairs of cell lines. Since loss of ...
essential genes is uniformly toxic in CRISPR-based screens, we also developed a small hairpin RNA (shRNA) library targeting essential genes. These approaches uncovered a large set of proteins whose loss results in the selective reduction of K-Ras mutant cell growth. Pathway analysis revealed that many of these genes function in the mitochondria. For validation, we generated isogenic pairs of cell lines using CRISPR-based genome engineering, which confirmed the dependency of K-Ras mutant cells on these mitochondrial pathways. Finally, we found that mitochondrial inhibitors reduce the growth of K-Ras mutant tumors in vivo, aiding in the advancement of strategies to target K-Ras-driven malignancy.
Mesh Terms:
Animals, Cell Line, Cell Proliferation, Clustered Regularly Interspaced Short Palindromic Repeats, Female, Genes, ras, HCT116 Cells, Humans, Hydrazones, Mice, Mice, Inbred BALB C, Minocycline, Mutation, NADH Dehydrogenase, Proto-Oncogene Proteins, Triazoles, Xenograft Model Antitumor Assays
Cell Rep
Date: Jul. 11, 2017
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