Tyrosine kinase inhibition in leukemia induces an altered metabolic state sensitive to mitochondrial perturbations

Clin Cancer Res. 2015 Mar 15;21(6):1360-72. doi: 10.1158/1078-0432.CCR-14-2146. Epub 2014 Dec 29.


Purpose: Although tyrosine kinase inhibitors (TKI) can be effective therapies for leukemia, they fail to fully eliminate leukemic cells and achieve durable remissions for many patients with advanced BCR-ABL(+) leukemias or acute myelogenous leukemia (AML). Through a large-scale synthetic lethal RNAi screen, we identified pyruvate dehydrogenase, the limiting enzyme for pyruvate entry into the mitochondrial tricarboxylic acid cycle, as critical for the survival of chronic myelogenous leukemia (CML) cells upon BCR-ABL inhibition. Here, we examined the role of mitochondrial metabolism in the survival of Ph(+) leukemia and AML upon TK inhibition.

Experimental design: Ph(+) cancer cell lines, AML cell lines, leukemia xenografts, cord blood, and patient samples were examined.

Results: We showed that the mitochondrial ATP-synthase inhibitor oligomycin-A greatly sensitized leukemia cells to TKI in vitro. Surprisingly, oligomycin-A sensitized leukemia cells to BCR-ABL inhibition at concentrations of 100- to 1,000-fold below those required for inhibition of respiration. Oligomycin-A treatment rapidly led to mitochondrial membrane depolarization and reduced ATP levels, and promoted superoxide production and leukemia cell apoptosis when combined with TKI. Importantly, oligomycin-A enhanced elimination of BCR-ABL(+) leukemia cells by TKI in a mouse model and in primary blast crisis CML samples. Moreover, oligomycin-A also greatly potentiated the elimination of FLT3-dependent AML cells when combined with an FLT3 TKI, both in vitro and in vivo.

Conclusions: TKI therapy in leukemia cells creates a novel metabolic state that is highly sensitive to particular mitochondrial perturbations. Targeting mitochondrial metabolism as an adjuvant therapy could therefore improve therapeutic responses to TKI for patients with BCR-ABL(+) and FLT3(ITD) leukemias.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Dihydrolipoyllysine-Residue Acetyltransferase / genetics
  • Disease Models, Animal
  • Female
  • Fusion Proteins, bcr-abl / metabolism
  • Humans
  • Imatinib Mesylate / pharmacology
  • Ketone Oxidoreductases / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proton-Translocating ATPases / antagonists & inhibitors*
  • Oligomycins / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • RNA Interference
  • RNA, Small Interfering
  • Superoxides / metabolism
  • fms-Like Tyrosine Kinase 3 / genetics*
  • fms-Like Tyrosine Kinase 3 / metabolism


  • Mitochondrial Proteins
  • Oligomycins
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • oligomycin A
  • Superoxides
  • Imatinib Mesylate
  • Ketone Oxidoreductases
  • pyruvate dehydrogenase (NADP+)
  • Dihydrolipoyllysine-Residue Acetyltransferase
  • Dlat protein, mouse
  • Flt3 protein, mouse
  • Protein-Tyrosine Kinases
  • fms-Like Tyrosine Kinase 3
  • Fusion Proteins, bcr-abl
  • Mitochondrial Proton-Translocating ATPases