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PDGFRA alterations in cancer: characterization of a gain-of-function V536E transmembrane mutant as well as loss-of-function and passenger mutations

Oncogene volume 33, pages 2568–2576 (2014)Cite this article

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Abstract

Activating mutations in the platelet-derived growth factor (PDGF) receptor alpha (PDGFRA) have been described in patients with gastrointestinal stromal tumors or myeloid malignancies associated with hypereosinophilia. These patients respond well to imatinib mesylate, raising the question as to whether patients with a PDGF receptor mutation in other tumor types should receive a tyrosine kinase inhibitor treatment. We characterized 10 novel somatic point mutations in PDGFRA that have been reported in isolated cases of glioblastoma, melanoma, acute myeloid leukemia, peripheral nerve sheath tumors and neuroendocrine carcinoma. The PDGFRA transmembrane domain mutation V536E stimulated Ba/F3 cell growth and signaling via ERK and STAT5 in the absence of ligand. This mutant, identified in glioblastoma, was strongly inhibited by imatinib. Modeling suggested that the mutation modulates the packing of the transmembrane domain helices in the receptor dimer. By contrast, two mutations in highly conserved residues affected the receptor traffic to the cell surface or kinase activity, thereby preventing the response to PDGF. The other mutations had no significant impact on the receptor activity. This functional analysis matched the predictions of SIFT and PolyPhen for only five mutations and these algorithms do not discriminate gain from loss of function. Finally, an E996K variant that had been identified in a melanoma cell line was not expressed in these cells. Altogether, several newly identified PDGFRA mutations do not activate the receptor and may therefore represent passenger mutations. Our results also underline the importance of characterizing novel kinase alterations in cancer patients.

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Acknowledgements

We thank Francis Brasseur (Ludwig Institute for Cancer Research, Brussels, Belgium) for the LB373-MEL cell line and Stefan Constantinescu (de Duve Institute) for advices. This work was supported by the Salus Sanguinis Foundation and a grant from ‘Action de Recherches Concertées’ (Communauté Française de Belgique, Belgium).

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Authors and Affiliations

  1. de Duve Institute, Université catholique de Louvain, Brussels, Belgium

    A I Velghe, S Van Cauwenberghe, C P Montano-Almendras, S Charni, A Essaghir & J-B Demoulin

  2. Department of Structural and Computational Biology, Max F Perutz Laboratories, University of Vienna, Vienna, Austria

    A A Polyansky

  3. MM Shemyakin and Yu A Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia

    A A Polyansky

  4. Department of Molecular Biology, Umeå University, Umeå, Sweden

    D Chand & B Hallberg

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Velghe, A., Van Cauwenberghe, S., Polyansky, A. et al. PDGFRA alterations in cancer: characterization of a gain-of-function V536E transmembrane mutant as well as loss-of-function and passenger mutations. Oncogene 33, 2568–2576 (2014). https://doi.org/10.1038/onc.2013.218

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