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

doi:10.1016/j.ccr.2011.12.024

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

Department of Chemistry and Chemical Biology

Research output: Contribution to journal › Article › peer-review

337 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 language	English
Pages (from-to)	227-239
Number of pages	13
Journal	Cancer Cell
Volume	21
Issue number	2
DOIs	https://doi.org/10.1016/j.ccr.2011.12.024
State	Published - 14 Feb 2012

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title = "Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells",

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.",

author = "Taru Muranen and Selfors, \{Laura M.\} and Worster, \{Devin T.\} and Iwanicki, \{Marcin P.\} and Loling Song and Morales, \{Fabiana C.\} and Sizhen Gao and Mills, \{Gordon B.\} and Brugge, \{Joan S.\}",

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AU - Muranen, Taru

AU - Selfors, Laura M.

AU - Worster, Devin T.

AU - Iwanicki, Marcin P.

AU - Song, Loling

AU - Morales, Fabiana C.

AU - Gao, Sizhen

AU - Mills, Gordon B.

AU - Brugge, Joan S.

PY - 2012/2/14

Y1 - 2012/2/14

N2 - 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.

AB - 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.

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JO - Cancer Cell

JF - Cancer Cell

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ER -

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

Abstract

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