CDK1 Is a synthetic lethal target for KRAS mutant tumours

Sara Costa-Cabral, Rachel Brough, Asha Konde, Marieke Aarts, James Campbel, Eliana Marinari, Jenna Riffell, Alberto Bardelli, Christopher Torrance, Christopher J. Lord, Alan Ashworth

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Activating KRAS mutations are found in approximately 20% of human cancers but no RASdirected 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.

Original languageEnglish
Article numbere0149099
JournalPLoS One
Volume11
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

Fingerprint

lethal genes
Tumors
Cells
mutants
neoplasms
mutation
Amino Acids
Colorectal Neoplasms
Neoplasms
amino acids
cyclin-dependent kinase
Cyclin-Dependent Kinases
small interfering RNA
Heterografts
interphase
Small Interfering RNA
Mutation
S Phase
Modulation
therapeutics

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Costa-Cabral, S., Brough, R., Konde, A., Aarts, M., Campbel, J., Marinari, E., ... Ashworth, A. (2016). CDK1 Is a synthetic lethal target for KRAS mutant tumours. PLoS One, 11(2), [e0149099]. https://doi.org/10.1371/journal.pone.0149099

CDK1 Is a synthetic lethal target for KRAS mutant tumours. / Costa-Cabral, Sara; Brough, Rachel; Konde, Asha; Aarts, Marieke; Campbel, James; Marinari, Eliana; Riffell, Jenna; Bardelli, Alberto; Torrance, Christopher; Lord, Christopher J.; Ashworth, Alan.

In: PLoS One, Vol. 11, No. 2, e0149099, 01.02.2016.

Research output: Contribution to journalArticle

Costa-Cabral, S, Brough, R, Konde, A, Aarts, M, Campbel, J, Marinari, E, Riffell, J, Bardelli, A, Torrance, C, Lord, CJ & Ashworth, A 2016, 'CDK1 Is a synthetic lethal target for KRAS mutant tumours', PLoS One, vol. 11, no. 2, e0149099. https://doi.org/10.1371/journal.pone.0149099
Costa-Cabral S, Brough R, Konde A, Aarts M, Campbel J, Marinari E et al. CDK1 Is a synthetic lethal target for KRAS mutant tumours. PLoS One. 2016 Feb 1;11(2). e0149099. https://doi.org/10.1371/journal.pone.0149099
Costa-Cabral, Sara ; Brough, Rachel ; Konde, Asha ; Aarts, Marieke ; Campbel, James ; Marinari, Eliana ; Riffell, Jenna ; Bardelli, Alberto ; Torrance, Christopher ; Lord, Christopher J. ; Ashworth, Alan. / CDK1 Is a synthetic lethal target for KRAS mutant tumours. In: PLoS One. 2016 ; Vol. 11, No. 2.
@article{82d2031e2650469baa6871754fb9c7cd,
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 RASdirected 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.",
author = "Sara Costa-Cabral and Rachel Brough and Asha Konde and Marieke Aarts and James Campbel and Eliana Marinari and Jenna Riffell and Alberto Bardelli and Christopher Torrance and Lord, {Christopher J.} and Alan Ashworth",
year = "2016",
month = "2",
day = "1",
doi = "10.1371/journal.pone.0149099",
language = "English",
volume = "11",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "2",

}

TY - JOUR

T1 - CDK1 Is a synthetic lethal target for KRAS mutant tumours

AU - Costa-Cabral, Sara

AU - Brough, Rachel

AU - Konde, Asha

AU - Aarts, Marieke

AU - Campbel, James

AU - Marinari, Eliana

AU - Riffell, Jenna

AU - Bardelli, Alberto

AU - Torrance, Christopher

AU - Lord, Christopher J.

AU - Ashworth, Alan

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Activating KRAS mutations are found in approximately 20% of human cancers but no RASdirected 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.

AB - Activating KRAS mutations are found in approximately 20% of human cancers but no RASdirected 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.

UR - http://www.scopus.com/inward/record.url?scp=84978676921&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978676921&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0149099

DO - 10.1371/journal.pone.0149099

M3 - Article

AN - SCOPUS:84978676921

VL - 11

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 2

M1 - e0149099

ER -