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Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells

Oncogene volume 34, pages 2167–2177 (2015)Cite this article

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Abstract

Somatic alterations of fibroblast growth factor receptors (FGFRs) have been described in a wide range of malignancies. A number of anti-FGFR therapies are currently under investigation in clinical trials for subjects with FGFR gene amplifications, mutations and translocations. Here, we develop cell line models of acquired resistance to FGFR inhibition by exposure of cell lines harboring FGFR3 gene amplification and translocation to the selective FGFR inhibitor BGJ398 and multitargeted FGFR inhibitor ponatinib. We show that the acquisition of resistance is rapid, reversible and characterized by an epithelial to mesenchymal transition and a switch from dependency on FGFR3 to ERBB family members. Acquired resistance was associated with demonstrable changes in gene expression including increased production of ERBB2/3 ligands, which were sufficient to drive resistance in the setting of FGFR3 dependency but not dependency on other FGFR family members. These data support the concept that activation of ERBB family members is sufficient to bypass dependency on FGFR3 and suggest that concurrent inhibition of these two pathways may be desirable when targeting FGFR3-dependent cancers.

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Acknowledgements

PSH is supported by NCI K08 CA163677, the V Foundation the Stephen D and Alice Cutler Fund. We thank M Meyerson for assisting with the planning of this study. JW is supported by NSFC 81202746 and CSC.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    J Wang, O Mikse, R G Liao, Y Li, P A Janne, K-k Wong & P S Hammerman

  2. Department of Integrative Medicine and Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China

    J Wang

  3. Broad Institute of Harvard and MIT, Cambridge, MA, USA

    R G Liao, Y Li & P S Hammerman

  4. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    L Tan & N S Gray

  5. Belfer Institute of Applied Cancer Sciences, Boston, MA, USA

    P A Janne & K-k Wong

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  1. J Wang
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Correspondence to P S Hammerman.

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PSH reports consulting fees from ARIAD, ImClone, Janssen and Molecular MD. The remaining authors declare no conflict of interest.

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Wang, J., Mikse, O., Liao, R. et al. Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells. Oncogene 34, 2167–2177 (2015). https://doi.org/10.1038/onc.2014.161

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