Reference - Detail
|Author||Weigelt B, Warne PH, Lambros MB, Reis-Filho JS, Downward J.|
|Title||PI3K pathway dependencies in endometrioid endometrial cancer cell lines.|
|Journal||Clin Cancer Res|
PURPOSE:Endometrioid endometrial cancers (EEC) frequently harbor coexisting mutations in phosphoinositide 3-kinase (PI3K) pathway genes, including PTEN, PIK3CA, PIK3R1, and KRAS. We sought to define the genetic determinants of PI3K pathway inhibitor response in EEC cells, and whether PTEN-mutant EEC cell lines rely on p110β signaling for survival.
EXPERIMENTAL DESIGN:Twenty-four human EEC cell lines were characterized for their mutation profile and activation state of PI3K and mitogen-activated protein kinase (MAPK) signaling pathway proteins. Cells were treated with pan-class I PI3K, p110α, and p110β isoform-specific, allosteric mTOR, mTOR kinase, dual PI3K/mTOR, mitogen-activated protein/extracellular signal-regulated kinase (MEK), and RAF inhibitors. RNA interference (RNAi) was used to assess effects of KRAS silencing in EEC cells.
RESULTS:EEC cell lines harboring PIK3CA and PTEN mutations were selectively sensitive to the pan-class I PI3K inhibitor GDC-0941 and allosteric mTOR inhibitor temsirolimus, respectively. Subsets of EEC cells with concurrent PIK3CA and/or PTEN and KRAS mutations were sensitive to PI3K pathway inhibition, and only 2 of 6 KRAS-mutant cell lines showed response to MEK inhibition. KRAS RNAi silencing did not induce apoptosis in KRAS-mutant EEC cells. PTEN-mutant EEC cell lines were resistant to the p110β inhibitors GSK2636771 and AZD6482, and only in combination with the p110α selective inhibitor A66 was a decrease in cell viability observed.
CONCLUSIONS:Targeted pan-PI3K and mTOR inhibition in EEC cells may be most effective in PIK3CA- and PTEN-mutant tumors, respectively, even in a subset of EECs concurrently harboring KRAS mutations. Inhibition of p110β alone may not be sufficient to sensitize PTEN-mutant EEC cells and combination with other targeted agents may be required.
|MeSH||Apoptosis / drug effects Apoptosis / genetics Cell Line, Tumor Class Ia Phosphatidylinositol 3-Kinase / genetics Class Ia Phosphatidylinositol 3-Kinase / metabolism Endometrial Neoplasms / genetics Endometrial Neoplasms / metabolism* Female Gene Silencing Humans Indazoles / pharmacology Mutation PTEN Phosphohydrolase / genetics PTEN Phosphohydrolase / metabolism Phosphatidylinositol 3-Kinases / genetics Phosphatidylinositol 3-Kinases / metabolism* Phosphoinositide-3 Kinase Inhibitors Proto-Oncogene Proteins / genetics Proto-Oncogene Proteins / metabolism Proto-Oncogene Proteins c-akt / metabolism Proto-Oncogene Proteins p21(ras) Signal Transduction* / drug effects Sulfonamides / pharmacology ras Proteins / genetics ras Proteins / metabolism|
|Human and Animal Cells|