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 Mills, Joan S. Brugge

Research output: Contribution to journalArticle

238 Citations (Scopus)

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
Externally publishedYes

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Phosphatidylinositol 3-Kinases
Neoplasms
Drug Combinations
Pharmaceutical Preparations
Ovarian Neoplasms
Intercellular Signaling Peptides and Proteins
Up-Regulation
Food
Proteins
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Muranen, T., Selfors, L. M., Worster, D. T., Iwanicki, M. P., Song, L., Morales, F. C., ... Brugge, J. S. (2012). Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells. Cancer Cell, 21(2), 227-239. https://doi.org/10.1016/j.ccr.2011.12.024

Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells. / Muranen, Taru; Selfors, Laura M.; Worster, Devin T.; Iwanicki, Marcin P.; Song, Loling; Morales, Fabiana C.; Gao, Sizhen; Mills, Gordon; Brugge, Joan S.

In: Cancer Cell, Vol. 21, No. 2, 14.02.2012, p. 227-239.

Research output: Contribution to journalArticle

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
Muranen T, Selfors LM, Worster DT, Iwanicki MP, Song L, Morales FC et al. Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells. Cancer Cell. 2012 Feb 14;21(2):227-239. https://doi.org/10.1016/j.ccr.2011.12.024
Muranen, Taru ; Selfors, Laura M. ; Worster, Devin T. ; Iwanicki, Marcin P. ; Song, Loling ; Morales, Fabiana C. ; Gao, Sizhen ; Mills, Gordon ; Brugge, Joan S. / Inhibition of PI3K/mTOR Leads to Adaptive Resistance in Matrix-Attached Cancer Cells. In: Cancer Cell. 2012 ; Vol. 21, No. 2. pp. 227-239.
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