PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

Sci Rep. 2017 Feb 21;7:43013. doi: 10.1038/srep43013.

Abstract

Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN-loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Drug Synergism
  • Everolimus / pharmacology
  • Female
  • Humans
  • Janus Kinase 1 / genetics
  • Janus Kinase 1 / metabolism
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / metabolism*
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • PTEN Phosphohydrolase / antagonists & inhibitors
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyridones / pharmacology
  • Pyrimidinones / pharmacology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyridones
  • Pyrimidinones
  • RNA, Small Interfering
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • trametinib
  • Everolimus
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • JAK1 protein, human
  • Janus Kinase 1
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human