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Sci Signal. 2016 Sep 13;9(445):ra90. doi: 10.1126/scisignal.aac9704.

CHK1 as a therapeutic target to bypass chemoresistance in AML.

Author information

1
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.
2
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.
3
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.
4
Département d'Epidémiologie, Economie de la Santé et Santé Publique, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
5
Service d'hématologie, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.
6
Laboratoire d'Excellence Toulouse Cancer Labex TOUCAN, Cancer Research Center of Toulouse, Inserm U1037, CNRS ERL5294, Toulouse, France. Université Paul Sabatier, Toulouse, France.
7
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.
8
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.
9
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.

Abstract

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.

PMID:
27625304
DOI:
10.1126/scisignal.aac9704
[Indexed for MEDLINE]

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