Glutaminase inhibition improves FLT3 inhibitor therapy for acute myeloid leukemia

Exp Hematol. 2018 Feb;58:52-58. doi: 10.1016/j.exphem.2017.09.007. Epub 2017 Sep 22.

Abstract

Acute myeloid leukemia (AML) is a blood cancer that is poorly responsive to conventional cytotoxic chemotherapy and a diagnosis of AML is usually fatal. More effective and better-tolerated therapies for AML are desperately needed. Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are one of the most frequently observed genetic defects in AML. FLT3 inhibitors have shown impressive anti-leukemic activity in clinical trials; however, sustained remissions using these inhibitors as monotherapy have not been achieved. Our previous studies have implicated impaired glutamine metabolism in response to FLT3 inhibitors as a dominant factor causing AML cell death. In this study, we have employed metabolic flux analysis to examine the effects of FLT3 inhibition on glutamine utilization in FLT3-mutated AML cells using stable isotope tracers. We found that the FLT3 inhibitor AC220 inhibited glutamine flux into the antioxidant factor glutathione profoundly due to defective glutamine import. We also found that the glutaminase inhibitor CB-839 similarly impaired glutathione production by effectively blocking flux of glutamine into glutamate. Moreover, the combination of AC220 with CB-839 synergized to deplete glutathione, induce mitochondrial reactive oxygen species, and cause loss of viability through apoptotic cell death. In vivo, glutaminase inhibition with CB-839 facilitated leukemic cell elimination by AC220 and improved survival significantly in a patient-derived xenograft AML mouse model. Therefore, targeting glutaminase in combination with FLT3 may represent an effective therapeutic strategy for improving treatment of FLT3-mutated AML.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzeneacetamides / pharmacology*
  • Benzothiazoles / pharmacology*
  • Cell Line, Tumor
  • Female
  • Glutamic Acid / genetics
  • Glutamic Acid / metabolism
  • Glutaminase* / antagonists & inhibitors
  • Glutaminase* / genetics
  • Glutaminase* / metabolism
  • Glutamine / genetics
  • Glutamine / metabolism
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / enzymology
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Phenylurea Compounds / pharmacology*
  • Thiadiazoles / pharmacology*
  • Xenograft Model Antitumor Assays
  • fms-Like Tyrosine Kinase 3* / antagonists & inhibitors
  • fms-Like Tyrosine Kinase 3* / genetics
  • fms-Like Tyrosine Kinase 3* / metabolism

Substances

  • Benzeneacetamides
  • Benzothiazoles
  • CB-839
  • Phenylurea Compounds
  • Thiadiazoles
  • Glutamine
  • Glutamic Acid
  • quizartinib
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3
  • Glutaminase