Laure David et al in Science:
A pair of papers provides new hope for patients with acute myeloid leukemia (AML) by showing that the DNA replication checkpoint pathway is a viable target for therapeutic intervention. By integrating survival data from 198 treated AML patients with gene expression data for genes encoding proteins involved in the regulation of DNA replication, David et al. identified the CHEK1 gene and its product, the DNA replication checkpoint kinase CHK1, as both a prognostic indicator of survival and a therapeutic target to overcome resistance to the current standard of chemotherapy. The patients had all received standard-of-care chemotherapy. Patients with high expression of CHEK1 in their AML cells had reduced survival, and AML patient cells with high CHK1 abundance were resistant to the toxic effects of the DNA replication inhibitor cytarabine. CHK1 is activated by the kinase ATR in response to DNA replication stress arising from DNA damage. The identification of CHEK1 expression as high in lymphomas and leukemias, including AML, prompted Morgado-Palacin et al. to investigate targeting ATR and ATM, the most upstream kinases in the DNA damage response, as possible AML therapies. AML cells with oncogenic rearrangements in MLL are particularly resistant to genotoxic therapies that form the backbone of AML treatment. Inhibiting ATR resulted in death of AMLMLL cells in culture and exhibited antitumoral activity in AMLMLL mouse models. Inhibiting ATM also prolonged survival of the allograft mouse model, indicating that targeting the DNA damage response pathways alone or in combination with other chemotherapeutic agents may be beneficial in patients with AML.
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