Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas

PLoS One. 2012;7(5):e37431. doi: 10.1371/journal.pone.0037431. Epub 2012 May 25.

Abstract

The PI3K (phosphatidylinositol-3-kinase)/mTOR (mammalian target of rapamycin) pathway is frequently activated in endometrial cancer through various PI3K/AKT-activating genetic alterations. We examined the antitumor effect of NVP-BEZ235--a dual PI3K/mTOR inhibitor--and RAD001--an mTOR inhibitor--in 13 endometrial cancer cell lines, all of which possess one or more alterations in PTEN, PIK3CA, and K-Ras. We also combined these compounds with a MAPK pathway inhibitor (PD98059 or UO126) in cell lines with K-Ras alterations (mutations or amplification). PTEN mutant cell lines without K-Ras alterations (n = 9) were more sensitive to both RAD001 and NVP-BEZ235 than were cell lines with K-Ras alterations (n = 4). Dose-dependent growth suppression was more drastically induced by NVP-BEZ235 than by RAD001 in the sensitive cell lines. G1 arrest was induced by NVP-BEZ235 in a dose-dependent manner. We observed in vivo antitumor activity of both RAD001 and NVP-BEZ235 in nude mice. The presence of a MEK inhibitor, PD98059 or UO126, sensitized the K-Ras mutant cells to NVP-BEZ235. Robust growth suppression by NVP-BEZ235 suggests that a dual PI3K/mTOR inhibitor is a promising therapeutic for endometrial carcinomas. Our data suggest that mutational statuses of PTEN and K-Ras might be useful predictors of sensitivity to NVP-BEZ235 in certain endometrial carcinomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Class I Phosphatidylinositol 3-Kinases
  • Dose-Response Relationship, Drug
  • Endometrial Neoplasms / drug therapy
  • Endometrial Neoplasms / genetics*
  • Everolimus
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Genotype*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology*
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation
  • PTEN Phosphohydrolase / genetics
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Quinolines / administration & dosage
  • Quinolines / pharmacology*
  • Ribosomal Protein S6 Kinases / metabolism
  • Sirolimus / administration & dosage
  • Sirolimus / analogs & derivatives*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Xenograft Model Antitumor Assays
  • ras Proteins / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins
  • Quinolines
  • Everolimus
  • TOR Serine-Threonine Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • Glycogen Synthase Kinase 3
  • PTEN Phosphohydrolase
  • ras Proteins
  • dactolisib
  • Sirolimus