Cytarabine-Resistant FLT3-ITD Leukemia Cells are Associated with TP53 Mutation and Multiple Pathway Alterations-Possible Therapeutic Efficacy of Cabozantinib

Int J Mol Sci. 2019 Mar 11;20(5):1230. doi: 10.3390/ijms20051230.

Abstract

Internal tandem duplication of FLT3 juxtamembrane domain (FLT3-ITD)-positive acute myeloid leukemia (AML) leads to poor clinical outcomes after chemotherapy. We aimed to establish a cytarabine-resistant line from FLT3-ITD-positive MV4-11 (MV4-11-P) cells and examine the development of resistance. The FLT3-ITD mutation was retained in MV4-11-R; however, the protein was underglycosylated and less phosphorylated in these cells. Moreover, the phosphorylation of ERK1/2, Akt, MEK1/2 and p53 increased in MV4-11-R. The levels of Mcl-1 and p53 proteins were also elevated in MV4-11-R. A p53 D281G mutant emerged in MV4-11-R, in addition to the pre-existing R248W mutation. MV4-11-P and MV4-11-R showed similar sensitivity to cabozantinib, sorafenib, and MK2206, whereas MV4-11-R showed resistance to CI-1040 and idarubicin. MV4-11-R resistance may be associated with inhibition of Akt phosphorylation, but not ERK phosphorylation, after exposure to these drugs. The multi-kinase inhibitor cabozantinib inhibited FLT3-ITD signaling in MV4-11-R cells and MV4-11-R-derived tumors in mice. Cabozantinib effectively inhibited tumor growth and prolonged survival time in mice bearing MV4-11-R-derived tumors. Together, our findings suggest that Mcl-1 and Akt phosphorylation are potential therapeutic targets for p53 mutants and that cabozantinib is an effective treatment in cytarabine-resistant FLT3-ITD-positive AML.

Keywords: Cytarabine; FLT3-ITD; acute myeloid leukemia; drug-resistance.

MeSH terms

  • Anilides / pharmacology
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Biomarkers
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cytarabine / pharmacology*
  • DNA Mutational Analysis
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / genetics*
  • Gene Deletion*
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Metabolic Networks and Pathways
  • Mutation*
  • Pyridines / pharmacology
  • Tandem Repeat Sequences*
  • Tumor Suppressor Protein p53 / genetics*
  • fms-Like Tyrosine Kinase 3 / genetics*

Substances

  • Anilides
  • Apoptosis Regulatory Proteins
  • Biomarkers
  • Pyridines
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Cytarabine
  • cabozantinib
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3