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.
['Martin|Timothy D|TD|', 'Cook|Danielle R|DR|', 'Choi|Mei Yuk|MY|', 'Li|Mamie Z|MZ|', 'Haigis|Kevin M|KM|', 'Elledge|Stephen J|SJ|']
D000818:Animals D002460:Cell Line D049109:Cell Proliferation D064112:Clustered Regularly Interspaced Short Palindromic Repeats D005260:Female D011905:Genes, ras D045325:HCT116 Cells D006801:Humans D006835:Hydrazones D051379:Mice D008807:Mice, Inbred BALB C D008911:Minocycline D009154:Mutation D009245:NADH Dehydrogenase D011518:Proto-Oncogene Proteins D000078304:Tigecycline D014230:Triazoles D023041:Xenograft Model Antitumor Assays
mitochondrial translation KRAS CRISPR shRNA mitochondria genetic screen mitoribosome oxidative phosphorylation synthetic lethal