Neomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapies

Carman K.M. Ip, Patrick K.S. Ng, Kang Jin Jeong, S. H. Shao, Zhenlin Ju, P. G. Leonard, Xu Hua, Christopher P. Vellano, Richard Woessner, Nidhi Sahni, Kenneth L. Scott, Gordon B. Mills

    Research output: Contribution to journalArticle

    9 Scopus citations

    Abstract

    Activation of platelet-derived growth factor receptor alpha (PDGFRA) by genomic aberrations contributes to tumor progression in several tumor types. In this study, we characterize 16 novel PDGFRA mutations identified from different tumor types and identify three previously uncharacterized activating mutations that promote cell survival and proliferation. PDGFRA Y288C, an extracellular domain mutation, is primarily high mannose glycosylated consistent with trapping in the endoplasmic reticulum (ER). Strikingly, PDGFRA Y288C is constitutively dimerized and phosphorylated in the absence of ligand suggesting that trapping in the ER or aberrant glycosylation is sufficient for receptor activation. Importantly, PDGFRA Y288C induces constitutive phosphorylation of Akt, ERK1/2, and STAT3. PDGFRA Y288C is resistant to PDGFR inhibitors but sensitive to PI3K/mTOR and MEK inhibitors consistent with pathway activation results. Our findings further highlight the importance of characterizing functional consequences of individual mutations for precision medicine.

    Original languageEnglish (US)
    Article number4583
    JournalNature communications
    Volume9
    Issue number1
    DOIs
    StatePublished - Dec 1 2018

    ASJC Scopus subject areas

    • Chemistry(all)
    • Biochemistry, Genetics and Molecular Biology(all)
    • Physics and Astronomy(all)

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    Ip, C. K. M., Ng, P. K. S., Jeong, K. J., Shao, S. H., Ju, Z., Leonard, P. G., Hua, X., Vellano, C. P., Woessner, R., Sahni, N., Scott, K. L., & Mills, G. B. (2018). Neomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapies. Nature communications, 9(1), [4583]. https://doi.org/10.1038/s41467-018-06949-w