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

作者：Martin Timothy D; Cook Danielle R; Choi Mei Yuk; Li Mamie Z; Haigis Kevin M; Elledge Stephen J

来源：Cell Reports, 2017, 20(2): 427-438.

DOI：10.1016/j.celrep.2017.06.061

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.

• 出版日期2017-7-11