MET and PI3K/mTOR as a potential combinatorial therapeutic target in malignant pleural mesothelioma

PLoS One. 2014 Sep 15;9(9):e105919. doi: 10.1371/journal.pone.0105919. eCollection 2014.

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. Studies have shown that both MET and its key downstream intracellular signaling partners, PI3K and mTOR, are overexpressed in MPM. Here we determined the combinatorial therapeutic efficacy of a new generation small molecule inhibitor of MET, ARQ 197, and dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 in mesothelioma cell and mouse xenograft models. Cell viability results show that mesothelioma cell lines were sensitive to ARQ 197, NVP-BEZ235 and GDC-0980 inhibitors. The combined use of ARQ 197 with either NVP-BEZ235 or GDC-0980, was synergistic (CI<1). Significant delay in wound healing was observed with ARQ 197 (p<0.001) with no added advantage of combining it with either NVP-BEZ235 or GDC-0980. ARQ 197 alone mainly induced apoptosis (20±2.36%) that was preceded by suppression of MAPK activity, while all the three suppressed cell cycle progression. Both GDC-0980 and NVP-BEZ235 strongly inhibited activities of PI3K and mTOR as evidenced from the phosphorylation status of AKT and S6 kinase. The above observation was further substantiated by the finding that a majority of the MPM archival samples tested revealed highly active AKT. While the single use of ARQ 197 and GDC-0980 inhibited significantly the growth of MPM xenografts (p<0.05, p<0.001 respectively) in mice, the combination of the above two drugs was highly synergistic (p<0.001). Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than the use of the drugs singly in suppressing MPM tumor growth and motility and therefore merit further translational studies.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Drug Synergism
  • Female
  • Humans
  • Imidazoles / pharmacology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Mesothelioma / drug therapy
  • Mesothelioma / genetics*
  • Mesothelioma, Malignant
  • Mice
  • Mice, Nude
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Pyrimidines / pharmacology
  • Pyrrolidinones / pharmacology
  • Quinolines / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Wound Healing / drug effects
  • Wound Healing / genetics
  • Xenograft Model Antitumor Assays

Substances

  • 1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
  • ARQ 197
  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyrimidines
  • Pyrrolidinones
  • Quinolines
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • dactolisib