A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast Cancer

Katrien Berns, Hugo M. Horlings, Bryan T. Hennessy, Mandy Madiredjo, E. Marielle Hijmans, Karin Beelen, Sabine C. Linn, Ana Maria Gonzalez-Angulo, Katherine Stemke-Hale, Michael Hauptmann, Roderick L. Beijersbergen, Gordon B. Mills, Marc J. van de Vijver, René Bernards

    Research output: Contribution to journalArticle

    1155 Scopus citations

    Abstract

    A large-scale RNA interference screen to discover genes involved in trastuzumab resistance in breast cancer identified only PTEN as a modulator of drug sensitivity. Oncogenic mutants of PIK3CA (activator of the same pathway and frequently mutated in breast cancer) also conferred resistance to trastuzumab in cell culture. In a cohort of 55 breast cancer patients, activation of the PI3K pathway, as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression, was associated with poor prognosis after trastuzumab therapy, and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone. Thus, assessment of PI3K pathway activation may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy.

    Original languageEnglish (US)
    Pages (from-to)395-402
    Number of pages8
    JournalCancer Cell
    Volume12
    Issue number4
    DOIs
    StatePublished - Oct 16 2007

    Keywords

    • CELLCYCLE

    ASJC Scopus subject areas

    • Oncology
    • Cell Biology
    • Cancer Research

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  • Cite this

    Berns, K., Horlings, H. M., Hennessy, B. T., Madiredjo, M., Hijmans, E. M., Beelen, K., Linn, S. C., Gonzalez-Angulo, A. M., Stemke-Hale, K., Hauptmann, M., Beijersbergen, R. L., Mills, G. B., van de Vijver, M. J., & Bernards, R. (2007). A Functional Genetic Approach Identifies the PI3K Pathway as a Major Determinant of Trastuzumab Resistance in Breast Cancer. Cancer Cell, 12(4), 395-402. https://doi.org/10.1016/j.ccr.2007.08.030