Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells

Taru Muranen, Laura M. Selfors, Devin T. Worster, Marcin P. Iwanicki, Loling Song, Fabiana C. Morales, Sizhen Gao, Gordon B. Mills, Joan S. Brugge

    Research output: Contribution to journalArticle

    260 Scopus citations

    Abstract

    The PI3K/mTOR-pathway is the most commonly dysregulated pathway in epithelial cancers and represents an important target for cancer therapeutics. Here, we show that dual inhibition of PI3K/mTOR in ovarian cancer-spheroids leads to death of inner matrix-deprived cells, whereas matrix-attached cells are resistant. This matrix-associated resistance is mediated by drug-induced upregulation of cellular survival programs that involve both FOXO-regulated transcription and cap-independent translation. Inhibition of any one of several upregulated proteins, including Bcl-2, EGFR, or IGF1R, abrogates resistance to PI3K/mTOR inhibition. These results demonstrate that acute adaptive responses to PI3K/mTOR inhibition in matrix-attached cells resemble well-conserved stress responses to nutrient and growth factor deprivation. Bypass of thisresistance mechanism through rational design of drug combinations could significantly enhance PI3K-targeted drug efficacy.

    Original languageEnglish (US)
    Pages (from-to)227-239
    Number of pages13
    JournalCancer Cell
    Volume21
    Issue number2
    DOIs
    StatePublished - Feb 14 2012

    ASJC Scopus subject areas

    • Oncology
    • Cell Biology
    • Cancer Research

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