title: Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities.
abstract: ATR and CHK1 maintain cancer cell survival under replication stress and inhibitors of both kinases are currently undergoing clinical trials. As ATR activity is increased after CHK1 inhibition, we hypothesized that this may indicate an increased reliance on ATR for survival. Indeed, we observe that replication stress induced by the CHK1 inhibitor AZD7762 results in replication catastrophe and apoptosis, when combined with the ATR inhibitor VE-821 specifically in cancer cells. Combined treatment with ATR and CHK1 inhibitors leads to replication fork arrest, ssDNA accumulation, replication collapse, and synergistic cell death in cancer cells in vitro and in vivo. Inhibition of CDK reversed replication stress and synthetic lethality, demonstrating that regulation of origin firing by ATR and CHK1 explains the synthetic lethality. In conclusion, this study exemplifies cancer-specific synthetic lethality between two proteins in the same pathway and raises the prospect of combining ATR and CHK1 inhibitors as promising cancer therapy.
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sanjiv
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Hagenkort
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Calderón-Montaño
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Koolmeister
authors.affiliation: Vertex Pharmaceuticals (Europe) Ltd., Abingdon, Oxfordshire OX14 4RW, UK.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Reaper
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden.
authors.forename: Oliver
authors.initials: O
authors.lastname: Mortusewicz
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden.
authors.forename: Sylvain A
authors.initials: SA
authors.lastname: Jacques
authors.affiliation: Laboratory Medicine, Karolinska Institutet, 171 21 Stockholm, Sweden.
authors.forename: Raoul V
authors.initials: RV
authors.lastname: Kuiper
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Scobie
authors.affiliation: Vertex Pharmaceuticals (Europe) Ltd., Abingdon, Oxfordshire OX14 4RW, UK.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Charlton
authors.affiliation: Vertex Pharmaceuticals (Europe) Ltd., Abingdon, Oxfordshire OX14 4RW, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Pollard
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden.
authors.forename: Ulrika Warpman
authors.initials: UW
authors.lastname: Berglund
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Altun
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 21 Stockholm, Sweden. Electronic address: thomas.helleday@scilifelab.se.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
mesh_terms: D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D006801:Humans; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D011494:Protein Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000071877:Checkpoint Kinase 1
keywords: ATR; CHK1; DNA damage; cancer; replication stress; synthetic lethality