title: CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours.
abstract: Activating KRAS mutations are found in approximately 20% of human cancers but no RAS-directed therapies are currently available. Here we describe a novel, robust, KRAS synthetic lethal interaction with the cyclin dependent kinase, CDK1. This was discovered using parallel siRNA screens in KRAS mutant and wild type colorectal isogenic tumour cells and subsequently validated in a genetically diverse panel of 26 colorectal and pancreatic tumour cell models. This established that the KRAS/CDK1 synthetic lethality applies in tumour cells with either amino acid position 12 (p.G12V, pG12D, p.G12S) or amino acid position 13 (p.G13D) KRAS mutations and can also be replicated in vivo in a xenograft model using a small molecule CDK1 inhibitor. Mechanistically, CDK1 inhibition caused a reduction in the S-phase fraction of KRAS mutant cells, an effect also characterised by modulation of Rb, a master control of the G1/S checkpoint. Taken together, these observations suggest that the KRAS/CDK1 interaction is a robust synthetic lethal effect worthy of further investigation.
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.|Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.
authors.forename: Sara
authors.initials: S
authors.lastname: Costa-Cabral
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.|Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.
authors.forename: Rachel
authors.initials: R
authors.lastname: Brough
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.|Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.
authors.forename: Asha
authors.initials: A
authors.lastname: Konde
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.|Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.
authors.forename: Marieke
authors.initials: M
authors.lastname: Aarts
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.|Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.
authors.forename: James
authors.initials: J
authors.lastname: Campbell
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.|Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.
authors.forename: Eliana
authors.initials: E
authors.lastname: Marinari
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.|Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.
authors.forename: Jenna
authors.initials: J
authors.lastname: Riffell
authors.affiliation: IFOM-FIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Horizon Discovery, 7100 Cambridge Research Park, Waterbeach, Cambridge, CB25 9TL, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Torrance
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.|Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.affiliation: The CRUK Gene Function Laboratory, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.|Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, United Kingdom.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016203:CDC2 Protein Kinase; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D005804:Genes, Lethal; D057166:High-Throughput Screening Assays; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D013844:Thiazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; D034741:RNA, Small Interfering; C512984:RO 3306; D013844:Thiazoles; C521840:AZD5438; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D016283:Proto-Oncogene Proteins p21(ras)