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A pair of studies suggest the DNA replication checkpoint pathway could be targeted to treat resistant acute myeloid leukemia (AML).
One study indicated that the kinase CHK1, which coordinates the DNA damage response and cell-cycle checkpoint response, might be targeted to overcome cytarabine resistance in AML.
The other study suggested that ATR, a kinase that activates CHK1, and ATM, a second upstream kinase in the DNA damage response, might be therapeutic targets in MLL-rearranged AML.
Both studies were published in Science Sigaling.
Laure David, of La Ligue Contre Le Cancer in Toulouse, France, and colleagues conducted this study.
The researchers integrated gene expression data with survival data from 198 AML patients who were previously treated with cytarabine-based chemotherapy.
The data showed that patients with high expression of CHEK1, the gene that encodes CHK1, had poor survival. And patient cells with high CHK1 abundance were resistant to cytarabine.
However, when the researchers exposed the cells with high CHK1 abundance to the CHK1 inhibitor SCH900776, they observed “reduced clonogenic ability and progression of DNA replication in the presence of cytarabine.”
The team therefore concluded that treatment with a CHK1 inhibitor might overcome resistance to cytarabine-based treatments in AML. They also said that monitoring CHEK1 expression in AML patients could potentially predict outcomes and reveal patients who might benefit from treatment with a CHK1 inhibitor.
The second study was conducted by Isabel Morgado-Palacin, of the Spanish National Cancer Research Center in Madrid, and colleagues.
The researchers investigated ATR, which is the primary sensor of DNA replication stress, and ATM, a kinase that senses DNA double-strand breaks, as possible therapeutic targets in MLL-rearranged AML.
The team found that inhibiting ATR induced chromosomal breakage and death in murine AML-MLL cells in vitro. And inhibiting ATR in vivo reduced the tumor burden and prevented tumors from growing.
The researchers also found that inhibiting ATM prolonged survival in the mouse model of AML-MLL, which suggests that both ATR and ATM might be therapeutic targets in MLL-rearranged AML.
