title: Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies.
abstract: Oncogenic mutations in RAS genes are very common in human cancer, resulting in cells with well-characterized selective advantages, but also less well-understood vulnerabilities. We have carried out a large-scale loss-of-function screen to identify genes that are required by KRAS-transformed colon cancer cells, but not by derivatives lacking this oncogene. Top-scoring genes were then tested in a larger panel of KRAS mutant and wild-type cancer cells. Cancer cells expressing oncogenic KRAS were found to be highly dependent on the transcription factor GATA2 and the DNA replication initiation regulator CDC6. Extending this analysis using a collection of drugs with known targets, we found that cancer cells with mutant KRAS showed selective addiction to proteasome function, as well as synthetic lethality with topoisomerase inhibition. Combination targeting of these functions caused improved killing of KRAS mutant cells relative to wild-type cells. These observations suggest novel targets and new ways of combining existing therapies for optimal effect in RAS mutant cancers, which are traditionally seen as being highly refractory to therapy.
authors.affiliation: Signal Transduction, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Steckel
authors.forename: Miriam
authors.initials: M
authors.lastname: Molina-Arcas
authors.forename: Britta
authors.initials: B
authors.lastname: Weigelt
authors.forename: Michaela
authors.initials: M
authors.lastname: Marani
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Warne
authors.forename: Hanna
authors.initials: H
authors.lastname: Kuznetsov
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelly
authors.forename: Becky
authors.initials: B
authors.lastname: Saunders
authors.forename: Michael
authors.initials: M
authors.lastname: Howell
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
authors.forename: David C
authors.initials: DC
authors.lastname: Hancock
mesh_terms: D000483:Alleles; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D019772:Topotecan / Q000494:pharmacology; D015533:Transcriptional Activation; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C103706:CDC6 protein, human; D018797:Cell Cycle Proteins; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C117307:KRAS protein, human; D009687:Nuclear Proteins; D061988:Proteasome Inhibitors; D011518:Proto-Oncogene Proteins; D011719:Pyrazines; D034741:RNA, Small Interfering; D059004:Topoisomerase I Inhibitors; D003841:Deoxycytidine; D000069286:Bortezomib; D019772:Topotecan; D046988:Proteasome Endopeptidase Complex; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D004264:DNA Topoisomerases, Type I; D000093542:Gemcitabine