Mutation in the FGFR1 tyrosine kinase domain or inactivation of PTEN is associated with acquired resistance to FGFR inhibitors in FGFR1-driven leukemia/lymphomas

Int J Cancer. 2017 Nov 1;141(9):1822-1829. doi: 10.1002/ijc.30848. Epub 2017 Jul 28.

Abstract

Stem cell leukemia/lymphoma syndrome (SCLL) is driven by constitutive activation of chimeric FGFR1 kinases generated by chromosome translocations. We have shown that FGFR inhibitors significantly suppress leukemia and lymphoma development in vivo, and cell viability in vitro. Since resistance to targeted therapies is a major reason for relapse, we developed FGFR1-overexpressing mouse and human cell lines that are resistant to the specific FGFR inhibitors AZD4547 and BGJ398, as well as non-specific inhibitors, such as ponatinib, TKI258 and E3810. Two mutually exclusive mechanisms for resistance were demonstrated; an activating V561M mutation in the FGFR1 kinase domain and mutational inactivation of PTEN resulting in increased PI3K/AKT activity. Ectopic expression of PTEN in the PTEN-mutant cells resensitizes them to FGFR inhibitors. Treatment of resistant cells with BGJ398, in combination with the BEZ235 PI3K inhibitor, shows an additive effect on growth in vitro and prolongs survival in xenograft models in vivo. These studies provide the first direct evidence for both the involvement of the FGFR1 V561M mutation and PTEN inactivation in the development of resistance in leukemias overexpressing chimeric FGFR1. These studies also provide a potential strategy to treat leukemias and lymphomas driven by FGFR1 activation that become resistant to FGFR1 inhibitors.

Keywords: AKT inhibitors; AML; FGFR1; FGFR1 mutations; PTEN deletion; inhibitors; resistance.

MeSH terms

  • Animals
  • Benzamides / administration & dosage
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Imidazoles / administration & dosage
  • Leukemia / drug therapy*
  • Leukemia / genetics
  • Leukemia / pathology
  • Lymphoma / drug therapy*
  • Lymphoma / genetics
  • Lymphoma / pathology
  • Mice
  • Mutation
  • Neoplastic Stem Cells
  • PTEN Phosphohydrolase / genetics*
  • Phenylurea Compounds / administration & dosage
  • Phosphatidylinositol 3-Kinases / genetics
  • Piperazines / administration & dosage
  • Protein Kinase Inhibitors / administration & dosage
  • Pyrazoles / administration & dosage
  • Pyrimidines / administration & dosage
  • Quinolines / administration & dosage
  • Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics*
  • Xenograft Model Antitumor Assays

Substances

  • AZD4547
  • Benzamides
  • Imidazoles
  • Phenylurea Compounds
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Quinolines
  • infigratinib
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • dactolisib