CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours.
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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.
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Cell Line, Tumor
Mice, Inbred BALB C
CDC2 Protein Kinase
RNA, Small Interfering
Protein Kinase Inhibitors
Xenograft Model Antitumor Assays
Gene Expression Regulation, Neoplastic
Dose-Response Relationship, Drug
Proto-Oncogene Proteins p21(ras)
High-Throughput Screening Assays
G1 Phase Cell Cycle Checkpoints
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PloS one, 2016, 11 (2), pp. e0149099 - ?