Dataset Information

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

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.

SUBMITTER: Traer E

PROVIDER: S-EPMC3945862 | biostudies-other | 2014 Mar

REPOSITORIES: biostudies-other

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

Traer Elie E Javidi-Sharifi Nathalie N Agarwal Anupriya A Dunlap Jennifer J English Isabel I Martinez Jacqueline J Tyner Jeffrey W JW Wong Melissa M Druker Brian J BJ

Blood 20140109 10

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 rece ...[more]

PMID: 24408322

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Dataset Information

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

Publications

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

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