CHK1 as a therapeutic target to bypass chemoresistance in AML.
The nucleoside analog cytarabine, an inhibitor of DNA replication fork progression that results in DNA damage, is currently used in the treatment of acute myeloid leukemia (AML). We explored the prognostic value of the expression of 72 genes involved in various aspects of DNA replication in a set of 198 AML patients treated by cytarabine-based chemotherapy. We unveiled that high expression of the DNA replication checkpoint gene CHEK1 is a prognostic marker associated with shorter overall, event-free, and relapse-free survivals and determined that the expression of CHEK1 can predict more frequent and earlier postremission relapse. CHEK1 encodes checkpoint kinase 1 (CHK1), which is activated by the kinase ATR when DNA replication is impaired by DNA damage. High abundance of CHK1 in AML patient cells correlated with higher clonogenic ability and more efficient DNA replication fork progression upon cytarabine treatment. Exposing the patient cells with the high abundance of CHK1 to SCH900776, an inhibitor of the kinase activity of CHK1, reduced clonogenic ability and progression of DNA replication in the presence of cytarabine. These results indicated that some AML cells rely on an efficient CHK1-mediated replication stress response for viability and that therapeutic strategies that inhibit CHK1 could extend current cytarabine-based treatments and overcome drug resistance. Furthermore, monitoring CHEK1 expression could be used both as a predictor of outcome and as a marker to select AML patients for CHK1 inhibitor treatments.
Equipe Labellisée, La Ligue Contre Le Cancer, Toulouse, France. Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France.
Laure
L
David
Equipe Labellisée, La Ligue Contre Le Cancer, Toulouse, France. Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France.
Anne
A
Fernandez-Vidal
Equipe Labellisée, La Ligue Contre Le Cancer, Toulouse, France. Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France. Service d'hématologie, Institut Universitaire du Cancer Toulouse-Oncopole, 1 avenue Irène Joliot-Curie, 31059 Toulouse, Cedex 9, France.
Sarah
S
Bertoli
Equipe Labellisée, La Ligue Contre Le Cancer, Toulouse, France. Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France.
Srdana
S
Grgurevic
Université Paul Sabatier, Toulouse, France. Département d'Epidémiologie, Economie de la Santé et Santé Publique, Centre Hospitalier Universitaire de Toulouse, Toulouse, France. Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1027, Epidémiologie et analyses en santé publique: Risques, maladies chroniques et handicaps, Faculté de médecine, Toulouse, France.
Benoît
B
Lepage
Département d'Epidémiologie, Economie de la Santé et Santé Publique, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
Dominique
D
Deshaies
Service d'hématologie, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.
Naïs
N
Prade
Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France.
Maëlle
M
Cartel
Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France.
Clément
C
Larrue
Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France.
Jean-Emmanuel
JE
Sarry
Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France. Service d'hématologie, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.
Eric
E
Delabesse
Equipe Labellisée, La Ligue Contre Le Cancer, Toulouse, France. Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France.
Christophe
C
Cazaux
Equipe Labellisée, La Ligue Contre Le Cancer, Toulouse, France. Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France.
Christine
C
Didier
Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France. Service d'hématologie, Institut Universitaire du Cancer Toulouse-Oncopole, 1 avenue Irène Joliot-Curie, 31059 Toulouse, Cedex 9, France. jean-sebastien.hoffmann@inserm.fr stephane.manenti@inserm.fr recher.christian@iuct-oncopole.fr.
Christian
C
Récher
Equipe Labellisée, La Ligue Contre Le Cancer, Toulouse, France. Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France. jean-sebastien.hoffmann@inserm.fr stephane.manenti@inserm.fr recher.christian@iuct-oncopole.fr.
Stéphane
S
Manenti
Equipe Labellisée, La Ligue Contre Le Cancer, Toulouse, France. Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France. jean-sebastien.hoffmann@inserm.fr stephane.manenti@inserm.fr recher.christian@iuct-oncopole.fr.
Jean-Sébastien
JS
Hoffmann
D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003561:Cytarabine / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
C559815:MK-8776; D009363:Neoplasm Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D003561:Cytarabine; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1