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

Sci Signal. 2016 Sep 13;9(445):ra91. doi: 10.1126/scisignal.aad8243.

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 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.

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins* / antagonists & inhibitors
  • Ataxia Telangiectasia Mutated Proteins* / genetics
  • Ataxia Telangiectasia Mutated Proteins* / metabolism
  • Gene Rearrangement*
  • Histone-Lysine N-Methyltransferase* / genetics
  • Histone-Lysine N-Methyltransferase* / metabolism
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / enzymology
  • Leukemia, Myeloid, Acute* / genetics
  • Mice
  • Myeloid-Lymphoid Leukemia Protein* / genetics
  • Myeloid-Lymphoid Leukemia Protein* / metabolism
  • Neoplasms, Experimental* / drug therapy
  • Neoplasms, Experimental* / enzymology
  • Neoplasms, Experimental* / genetics
  • Xenograft Model Antitumor Assays

Substances

  • KMT2A protein, human
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse
  • Atr protein, mouse
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse