Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML.
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 because of an attenuated response by p53, a protein that 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 AML(MLL) 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 AML(MLL) 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 AML(MLL) mice. Collectively, these data indicated that ATR or ATM inhibition represent potential therapeutic strategies for the treatment of AML, especially MLL-driven leukemias.
Genomic Instability Group; Spanish National Cancer Research Center (CNIO); Madrid 28029, Spain.
Isabel
I
Morgado-Palacin
Laboratory of Genome Integrity; National Cancer Institute; National Institutes of Health; Bethesda, MD 20892, USA.
Amanda
A
Day
Genomic Instability Group; Spanish National Cancer Research Center (CNIO); Madrid 28029, Spain.
Matilde
M
Murga
Genomic Instability Group; Spanish National Cancer Research Center (CNIO); Madrid 28029, Spain.
Vanesa
V
Lafarga
Genomic Instability Group; Spanish National Cancer Research Center (CNIO); Madrid 28029, Spain.
Marta Elena
ME
Anton
Laboratory of Genome Integrity; National Cancer Institute; National Institutes of Health; Bethesda, MD 20892, USA.
Anthony
A
Tubbs
Laboratory of Genome Integrity; National Cancer Institute; National Institutes of Health; Bethesda, MD 20892, USA.
Hua Tang
HT
Chen
Laboratory of Genome Integrity; National Cancer Institute; National Institutes of Health; Bethesda, MD 20892, USA.
Aysegul
A
Ergan
Laboratory of Genome Integrity; National Cancer Institute; National Institutes of Health; Bethesda, MD 20892, USA.
Rhonda
R
Anderson
Laboratory of Genome Integrity; National Cancer Institute; National Institutes of Health; Bethesda, MD 20892, USA.
Avinash
A
Bhandoola
AstraZeneca, Cambridge, CB4 0WG, UK.
Kurt G
KG
Pike
AstraZeneca, Cambridge, CB4 0WG, UK.
Bernard
B
Barlaam
AstraZeneca, Cambridge, CB4 0WG, UK.
Elaine
E
Cadogan
Human Oncology and Pathogenesis Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Xi
X
Wang
AstraZeneca, Cambridge, CB4 0WG, UK.
Andrew J
AJ
Pierce
Laboratory of Genome Integrity; National Cancer Institute; National Institutes of Health; Bethesda, MD 20892, USA.
Chad
C
Hubbard
Human Oncology and Pathogenesis Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Scott A
SA
Armstrong
Laboratory of Genome Integrity; National Cancer Institute; National Institutes of Health; Bethesda, MD 20892, USA.
André
A
Nussenzweig
Genomic Instability Group; Spanish National Cancer Research Center (CNIO); Madrid 28029, Spain.|Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17165 Solna, Sweden.
Oscar
O
Fernandez-Capetillo
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; C576897:Atr protein, mouse; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse