CDK1 Is a Synthetic Lethal Target for KRAS Mutant Tumours

PloS One
Sara Costa-CabralAlan Ashworth

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.

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Citations

Jul 28, 2016·Small GTPases·Xiufeng Pang, Mingyao Liu
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Apr 21, 2017·PloS One·Sara Costa-CabralAlan Ashworth
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Methods Mentioned

BETA
GTPases
transfection
flow
fluorescence-activated cell scan
flow cytometry
PCR
pull-down
Assay
xenografts

Software Mentioned

Click
BD FACSDiva

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