Application of pharmacologically induced transcriptomic profiles to interrogate PI3K-Akt-mTOR pathway activity associated with cancer patient prognosis

Oncotarget. 2016 Dec 20;7(51):84142-84154. doi: 10.18632/oncotarget.11776.

Abstract

The PI3K-Akt-mTOR signaling pathway has been identified as a key driver of carcinogenesis in several cancer types. As such, a major area of focus in cancer biology is the development of genomic biomarkers that can measure the activity level of the PI3K-Akt-mTOR pathway. In this study, we systematically estimate PI3K-Akt-mTOR pathway activity in breast primary tumor samples using transcriptomic profiles derived from drug treatment in MCF7 cell lines. We demonstrate that gene expression profiles derived from chemically-induced protein inhibition allows us to measure PI3K-Akt-mTOR pathway activity in patient tumor samples. With this approach, we predict prognosis and response to chemotherapy in cancer patients, and screen for potential pharmacological modulators of PI3K-Akt-mTOR pathway inhibitors.

Keywords: PI3K; computational biology; drug treatment; pharmacogenomics.

MeSH terms

  • Algorithms
  • Androstadienes / pharmacology
  • Antibiotics, Antineoplastic / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Chromones / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics*
  • HL-60 Cells
  • Humans
  • Kaplan-Meier Estimate
  • MCF-7 Cells
  • Models, Genetic
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Prognosis
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Transcriptome / drug effects
  • Transcriptome / genetics*
  • Wortmannin

Substances

  • Androstadienes
  • Antibiotics, Antineoplastic
  • Chromones
  • Morpholines
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Sirolimus
  • Wortmannin