Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia

Cancer Discov. 2017 May;7(5):494-505. doi: 10.1158/2159-8290.CD-16-1049. Epub 2017 Feb 13.

Abstract

Genomic studies in acute myeloid leukemias (AML) have identified mutations that drive altered DNA methylation, including TET2 and IDH2 Here, we show that models of AML resulting from TET2 or IDH2 mutations combined with FLT3ITD mutations are sensitive to 5-azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-azacytidine and AG-221 treatment induced an attenuation of aberrant DNA methylation and transcriptional output and resulted in a reduction in leukemic blasts consistent with antileukemic activity. These therapeutic benefits were associated with restoration of leukemic cell differentiation, and the normalization of hematopoiesis was derived from mutant cells. By contrast, combining AG-221 or 5-azacytidine with FLT3 inhibition resulted in a reduction in mutant allele burden, progressive recovery of normal hematopoiesis from non-mutant stem-progenitor cells, and reversal of dysregulated DNA methylation and transcriptional output. Together, our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML.Significance: AMLs with mutations in TET2 or IDH2 are sensitive to epigenetic therapy through inhibition of DNA methyltransferase activity by 5-azacytidine or inhibition of mutant IDH2 through AG-221. These inhibitors induce a differentiation response and can be used to inform mechanism-based combination therapy. Cancer Discov; 7(5); 494-505. ©2017 AACR.See related commentary by Thomas and Majeti, p. 459See related article by Yen et al., p. 478This article is highlighted in the In This Issue feature, p. 443.

MeSH terms

  • Aminopyridines / pharmacology
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Azacitidine / pharmacology
  • DNA Methylation / drug effects
  • DNA-Binding Proteins / genetics*
  • Epigenesis, Genetic / drug effects
  • Isocitrate Dehydrogenase / genetics*
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Mice
  • Mice, Mutant Strains
  • Molecular Targeted Therapy / methods*
  • Mutation
  • Proto-Oncogene Proteins / genetics*
  • Signal Transduction / drug effects
  • Triazines / pharmacology
  • fms-Like Tyrosine Kinase 3 / genetics

Substances

  • Aminopyridines
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Triazines
  • enasidenib
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, mouse
  • Tet2 protein, mouse
  • Flt3 protein, mouse
  • fms-Like Tyrosine Kinase 3
  • Azacitidine