CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours

• Published in: PloS one 2016-02, Vol.11 (2), p.e0149099
• Main Authors: Costa-Cabral, Sara, Brough, Rachel, Konde, Asha, Aarts, Marieke, Campbell, James, Marinari, Eliana, Riffell, Jenna, Bardelli, Alberto, Torrance, Christopher, Lord, Christopher J, Ashworth, Alan
• Format: Article
• Language: English
• Subjects: Acids; Amino acids; Analysis; Animals; Antineoplastic Agents - pharmacology; Biology and life sciences; Breast cancer; Causes of; CDC2 Protein Kinase; Cell culture; Cell cycle; Cell Line, Tumor; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Cyclin-dependent kinases; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - genetics; Cyclin-Dependent Kinases - metabolism; Dose-Response Relationship, Drug; Female; G1 Phase Cell Cycle Checkpoints - drug effects; Gene Expression Regulation, Neoplastic; Gene mutation; Genes; Genes, Lethal; Genetic aspects; Genetic screening; High-Throughput Screening Assays; Humans; Imidazoles - pharmacology; K-Ras protein; Kinases; Laboratories; Lethality; Medical research; Medicine and Health Sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Mutation; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - pathology; Physiological aspects; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Pyrimidines - pharmacology; Quinolines - pharmacology; Ras genes; Research parks; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; siRNA; Survival Analysis; Thiazoles - pharmacology; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0149099

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.