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

Cancer Cell. 2012 Feb 14;21(2):227-39. doi: 10.1016/j.ccr.2011.12.024.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / antagonists & inhibitors
  • Extracellular Matrix / drug effects
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Imidazoles / pharmacology
  • Mice
  • Ovarian Neoplasms / enzymology*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / 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

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • EIF4EBP1 protein, human
  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins
  • Proto-Oncogene Proteins c-bcl-2
  • Quinolines
  • RNA, Messenger
  • TOR Serine-Threonine Kinases
  • ErbB Receptors
  • Receptor, IGF Type 1
  • dactolisib

Associated data

  • GEO/GSE28992