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

Publication date: 11 July 2017
Source:Cell Reports, Volume 20, Issue 2
Author(s): Timothy D. Martin, Danielle R. Cook, Mei Yuk Choi, Mamie Z. Li, Kevin M. Haigis, Stephen J. Elledge
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.

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Teaser

Using CRISPR and shRNA-based screening approaches in isogenic cell lines, Martin et al. identify a requirement for mitochondrial translation in K-Ras mutant cell viability.


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