Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations

Elie Traer, Nathalie Javidi-Sharifi, Anupriya Agarwal, Jennifer Dunlap, Isabel English, Jacqueline Martinez, Jeffrey Tyner, Melissa Wong, Brian Druker

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Development of resistance to kinase inhibitors remains a clinical challenge. Kinase domain mutations are a common mechanism of resistance in chronic myeloid leukemia (CML), yet the mechanism of resistance in the absence of mutations remains unclear. We tested proteins from the bone marrow microenvironment and found that FGF2 promotes resistance to imatinib in vitro. Fibroblast growth factor 2 (FGF2) was uniquely capable of promoting growth in both short- and long-term assays through the FGF receptor 3/RAS/c-RAF/mitogen- activated protein kinase pathway. Resistance could be overcome with ponatinib, a multikinase inhibitor that targets BCR-ABL and FGF receptor. Clinically, we identified CML patients without kinase domain mutations who were resistant to multiple ABL kinase inhibitors and responded to ponatinib treatment. In comparison to CML patients with kinase domain mutations, these patients had increased FGF2 in their bone marrow when analyzed by immunohistochemistry. Moreover, FGF2 in the marrow decreased concurrently with response to ponatinib, further suggesting that FGF2-mediated resistance is interrupted by FGF receptor inhibition. These results illustrate the clinical importance of ligand-induced resistance to kinase inhibitors and support an approach of developing rational inhibitor combinations to circumvent resistance.

Original languageEnglish (US)
Pages (from-to)1516-1524
Number of pages9
JournalBlood
Volume123
Issue number10
DOIs
StatePublished - Mar 6 2014

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Fibroblast Growth Factor 2
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Phosphotransferases
Fibroblast Growth Factor Receptors
Mutation
Bone Marrow
Bone
Mitogen-Activated Protein Kinases
ponatinib
Assays
Immunohistochemistry
Ligands
Growth
Proteins

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations. / Traer, Elie; Javidi-Sharifi, Nathalie; Agarwal, Anupriya; Dunlap, Jennifer; English, Isabel; Martinez, Jacqueline; Tyner, Jeffrey; Wong, Melissa; Druker, Brian.

In: Blood, Vol. 123, No. 10, 06.03.2014, p. 1516-1524.

Research output: Contribution to journalArticle

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