Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL -rearranged AML

Abstract

Among the various subtypes of Acute Myeloid Leukemia (AML), those with chromosomal rearrangements of the MLL oncogene (AML-MLL) have a poor prognosis. AML-MLL tumor cells are resistant to current genotoxic therapies due to an attenuated response by p53, which induces cell cycle arrest and apoptosis in response to DNA damage. In addition to chemicals that damage DNA, efforts have focused on targeting DNA repair enzymes as a general chemotherapeutic approach to cancer treatment. Here, we found that inhibition of the kinase ATR, which is the primary sensor of DNA replication stress, induced chromosomal breakage and death of mouse AMLMLL cells (with an MLL-ENL fusion and a constitutively active N-RAS) independently of p53. Moreover, ATR inhibition as a single agent exhibited antitumoral activity, both reducing tumor burden after establishment and preventing tumors from growing, in an immunocompetent allograft mouse model of AMLMLL and in xenografts of a human AML-MLL cell line. We also found that inhibition of ATM, a kinase that senses DNA double-strand breaks, also promoted the survival of the AMLMLL mice. Collectively, these data indicated that ATR and ATM inhibition represent potential alternative therapeutic strategies for the treatment of AML, especially MLL-driven leukemias.

The DNA damage response pathway in normal hematopoiesis and malignancies

“…Notably, the ATR inhibitor AZ20 shows potent cytotoxic activity against AML-MLL cells in vitro, associated with activation of the DDR, increased replicative damage, and death independent of p53. Moreover, in vivo studies in mice performed with allografts of murine AML-MLL and xenografts of human AML cell line show that the ATR inhibitor, administered as monotherapy, markedly prolongs survival of mice and decreases tumor volume upon treatment with the ATR inhibitor [30]. Likewise, these in vivo studies with AML-MLL demonstrate that inhibition of ATM has a similar therapeutic activity [31].…”

“…Interestingly, however, ATR inhibition kills cancer cells, even those p53-deficient, by inducing accumulation of replication stress and premature mitotic entry from G2 phase, both being independent of p53. This evidence and the fact that Chk1, the downstream effector target of ATR, is overexpressed in many hematopoietic malignancies [30] and its abundance in AML negatively correlates with prognosis [31], has prompted investigations on the antitumor activity of ATR inhibition in AML-MLL. Notably, the ATR inhibitor AZ20 shows potent cytotoxic activity against AML-MLL cells in vitro, associated with activation of the DDR, increased replicative damage, and death independent of p53.…”

Cytosine Deaminase APOBEC3A Sensitizes Leukemia Cells to Inhibition of the DNA Replication Checkpoint

“…In vitro data have shown efficacy for ATRi in killing hematopoietic tumor cell lines with excessive oncogene-induced replication stress, ATM-deficiency, or in combination with oxidative stressors (21,48,49). ATRi is not frequently investigated as monotherapy in cancers without additional DDR defects, however the efficacy of ATRi was recently reported in a murine model of MLL-rearranged AML (50). Here we show that the replication checkpoint is activated by A3A in AML cells, and that A3A expression significantly increases the therapeutic index of ATR and Chk1 inhibitors.…”

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

“…Validation of therapeutic strategies to exploit RS has recently emerged from several studies (52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63). For example, an SL relationship was described between oncogene-induced RS by MYC activation and ATR loss in lymphomas (49).…”