@article{b531a31105204b67897c641a804a7ab7,
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.}",
note = "Funding Information: We thank Joel Leverson and Steve Elmore from Abbott Laboratories and Deepak Sampath from Genentech for ABT737 and GNE493 and for providing helpful advice on the in vivo study design. We thank Ed Cibas for fluid exudates; Nathanael Grey (Dana-Farber Cancer Institute) for Torin1; Dennis Slamon and Gottfried Konecny (University of California, Los Angeles) for the breast and ovarian cell lines; Yiling Lu (M.D. Anderson Cancer Center) for help with RPPA; Jennifer Waters and the Nikon Imaging Center at Harvard Medical School for microscopy; Gerhard Wagner (Harvard Medical School) for the CrPV-IRES plasmid; Richard Lloyd (Baylor College of Medicine) for the Bcl-2 IRES reporter; and Victor Velculescu for sharing PIK3CA mutation status on the ovarian cancer cell lines before publication. We also thank David Sabatini, Shomit Sengupta, Cheuk Leong, Alexandra Grassian, and Jonathan Coloff for their critical review of the manuscript and helpful discussions. These studies were supported by the Emil Aaltonen Foundation (T.M.), the Academy of Finland (T.M.), Stand Up to Cancer (SU2C) (J.B., G.M.), Ovarian SPORE Grant P50CA083639 (G.M.), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (J.B.), and National Cancer Institute Grant CA105134 (J.B.). ",
year = "2012",
month = feb,
day = "14",
doi = "10.1016/j.ccr.2011.12.024",
language = "English (US)",
volume = "21",
pages = "227--239",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "2",
}