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

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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
Publication statusPublished - Feb 14 2012
Externally publishedYes

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Muranen, T, Selfors, LM, Worster, DT, Iwanicki, MP, Song, L, Morales, FC, Gao, S, Mills, G & Brugge, JS 2012, 'Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells', Cancer Cell, vol. 21, no. 2, pp. 227-239. https://doi.org/10.1016/j.ccr.2011.12.024