Cabozantinib is selectively cytotoxic in acute myeloid leukemia cells with FLT3-internal tandem duplication (FLT3-ITD)

Cancer Lett. 2016 Jul 1;376(2):218-25. doi: 10.1016/j.canlet.2016.04.004. Epub 2016 Apr 6.

Abstract

Cabozantinib is an oral multikinase inhibitor that exhibits anti-tumor activity in several cancers. We found that cabozantinib was significantly cytotoxic to MV4-11 and Molm-13 cells that harbored FLT3-ITD, resulting in IC50 values of 2.4 nM and 2.0 nM, respectively. However, K562, OCI-AML3 and THP-1 (leukemia cell lines lacking FLT3-ITD) were resistant to cabozantinib, showing IC50 values in the micromolar range. Cabozantinib arrested MV4-11 cell growth at the G0/G1 phase within 24 h, which was associated with decreased phosphorylation of FLT3, STAT5, AKT and ERK. Additionally, cabozantinib induced MV4-11 cell apoptosis in a dose-dependent manner (as indicated by annexin V staining and high levels of cleaved caspase 3 and PARP-1), down-regulated the anti-apoptotic protein survivin and up-regulated the pro-apoptotic protein Bak. Thus, cabozantinib is selectively cytotoxic to leukemia cells with FLT3-ITD, causing cell-cycle arrest and apoptosis. In mouse xenograft model, cabozantinib significantly inhibited MV4-11 and Molm-13 tumor growth at a dosage of 10 mg/kg and showed longer survival rate. Clinical trials evaluating the efficacy of cabozantinib in acute myeloid leukemia (AML) with FLT3-ITD are warranted.

Keywords: Acute myeloid leukemia; Cabozantinib; FLT3-ITD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anilides / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Cycle Checkpoints / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Duplication*
  • Genetic Predisposition to Disease
  • HL-60 Cells
  • Humans
  • K562 Cells
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / enzymology
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Targeted Therapy
  • Phenotype
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / pharmacology*
  • Signal Transduction / drug effects
  • Time Factors
  • Tumor Burden / drug effects
  • U937 Cells
  • Xenograft Model Antitumor Assays
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
  • fms-Like Tyrosine Kinase 3 / genetics
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

  • Anilides
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Protein Kinase Inhibitors
  • Pyridines
  • cabozantinib
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3