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PMID: 22340595 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells.

Cancer cell ·Vol. 21 ·No. 2 ·2012-02-14 ·Pages 227-39

Muranen T, Selfors LM, Worster DT, Iwanicki MP, Song L, Morales FC, Gao S, Mills GB, Brugge JS

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 this resistance mechanism through rational design of drug combinations could significantly enhance PI3K-targeted drug efficacy.

MeSH Terms
Adaptor Proteins, Signal Transducing Animals Antineoplastic Agents/pharmacology Breast Neoplasms/enzymology,metabolism,pathology Cell Cycle Proteins Drug Resistance, Neoplasm ErbB Receptors/antagonists & inhibitors Extracellular Matrix/drug effects Female Gene Expression Regulation, Neoplastic Humans Imidazoles/pharmacology Mice Ovarian Neoplasms/enzymology,genetics,pathology Phosphoinositide-3 Kinase Inhibitors Phosphoproteins Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors Quinolines/pharmacology RNA, Messenger/metabolism Receptor, IGF Type 1/antagonists & inhibitors Signal Transduction Stress, Physiological TOR Serine-Threonine Kinases/antagonists & inhibitors Transplantation, Heterologous
Chemicals
Adaptor Proteins, Signal Transducing Antineoplastic Agents Cell Cycle Proteins EIF4EBP1 protein, human Imidazoles Phosphoinositide-3 Kinase Inhibitors Phosphoproteins Proto-Oncogene Proteins c-bcl-2 Quinolines RNA, Messenger ErbB Receptors Receptor, IGF Type 1 TOR Serine-Threonine Kinases dactolisib
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Muranen Taru
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA.
Selfors Laura M
Worster Devin T
Iwanicki Marcin P
Song Loling
Morales Fabiana C
Gao Sizhen
Mills Gordon B
Brugge Joan S
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2011.12.024
Published
2012-02-14
Pages
227-39
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3297962
Subset
IM
Grants
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · R01 CA105134-09 · United States
NCI NIH HHS · P50 CA098258 · United States
NCI NIH HHS · CA105134 · United States
NCI NIH HHS · R01 CA105134 · United States
NCI NIH HHS · P50 CA083639 · United States
NCI NIH HHS · P50CA083639 · United States
Databases
GEO
GSE28992
External Links
PubMed source DOI: 10.1016/j.ccr.2011.12.024 PMC Full Text View journal details
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