A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene.
Oncogenic mutations in the small GTPase Ras are highly prevalent in cancer, but an understanding of the vulnerabilities of these cancers is lacking. We undertook a genome-wide RNAi screen to identify synthetic lethal interactions with the KRAS oncogene. We discovered a diverse set of proteins whose depletion selectively impaired the viability of Ras mutant cells. Among these we observed a strong enrichment for genes with mitotic functions. We describe a pathway involving the mitotic kinase PLK1, the anaphase-promoting complex/cyclosome, and the proteasome that, when inhibited, results in prometaphase accumulation and the subsequent death of Ras mutant cells. Gene expression analysis indicates that reduced expression of genes in this pathway correlates with increased survival of patients bearing tumors with a Ras transcriptional signature. Our results suggest a previously underappreciated role for Ras in mitotic progression and demonstrate a pharmacologically tractable pathway for the potential treatment of cancers harboring Ras mutations.
Luo
Ji
J
Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
Emanuele
Michael J
MJ
Li
Danan
D
Creighton
Chad J
CJ
Schlabach
Michael R
MR
Westbrook
Thomas F
TF
Wong
Kwok-Kin
KK
Elledge
Stephen J
SJ
D000818:Animals; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism*; D005260:Female; D015894:Genome, Human; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D009154:Mutation; D009368:Neoplasm Transplantation; D061988:Proteasome Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D034622:RNA Interference; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
D018797:Cell Cycle Proteins; D061988:Proteasome Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000097869:Polo-Like Kinase 1; C117307:KRAS protein, human