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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology*
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Class I Phosphatidylinositol 3-Kinases
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Dose-Response Relationship, Drug
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Endometrial Neoplasms / drug therapy
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Endometrial Neoplasms / genetics*
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Everolimus
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Female
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G1 Phase Cell Cycle Checkpoints / drug effects
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Genotype*
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Imidazoles / administration & dosage
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Imidazoles / pharmacology*
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MAP Kinase Signaling System / drug effects
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mutation
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PTEN Phosphohydrolase / genetics
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Phosphatidylinositol 3-Kinases / genetics
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Quinolines / administration & dosage
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Quinolines / pharmacology*
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Ribosomal Protein S6 Kinases / metabolism
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Sirolimus / administration & dosage
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Sirolimus / analogs & derivatives*
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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Xenograft Model Antitumor Assays
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ras Proteins / genetics
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Imidazoles
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoproteins
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Quinolines
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Everolimus
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Class I Phosphatidylinositol 3-Kinases
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PIK3CA protein, human
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Glycogen Synthase Kinase 3 beta
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases
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TOR Serine-Threonine Kinases
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Glycogen Synthase Kinase 3
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PTEN Phosphohydrolase
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ras Proteins
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dactolisib
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Sirolimus