title: Comparison of the effects of the PI3K/mTOR inhibitors NVP-BEZ235 and GSK2126458 on tamoxifen-resistant breast cancer cells.
abstract: BACKGROUND
  Treatment with anti-estrogens or aromatase inhibitors is commonly used for patients with estrogen receptor-positive (ER+) breast cancers; however resistant disease develops almost inevitably, requiring a choice of secondary therapy. One possibility is to use inhibitors of the PI3K/mTOR pathway and several candidate drugs are in development. We examined the in vitro effects of two inhibitors of the PI3K/mTOR pathway on resistant MCF-7 cells.
  
  
  METHODS
  We cultured MCF-7 cells for prolonged periods either in the presence of the anti-estrogen tamoxifen (3 sub-lines) or in estrogen free medium (2 sub-lines) to mimic the effects of clinical treatment. We then analyzed the effects of two dual PI3K/mTOR phosphoinositide-3-kinase inhibitors, NVP-BEZ235 and GSK2126458, on the growth and signaling pathways of these MCF-7 sub-lines. The functional status of the PI3K, mTOR and ERK pathways was analyzed by measuring phosphorylation of AKT, p70S6K, rpS6 and ERK.
  
  
  RESULTS
  The derived sub-lines showed increased resistance to tamoxifen but none exhibited concomitantly increased sensitivity to the PI3K inhibitors. NVP-BEZ235 and GSK2126458 acted mainly by induction of cell cycle arrest, particularly in G1-phase, rather than by induction of apoptosis. The lines varied considerably in their utilization of the AKT, p70S6K and ERK pathways. NVP-BEZ235 and GSK2126458 inhibited AKT signaling but NVP-BEZ235 showed greater effects than GSK2126458 on p70S6K and rpS6 signaling with effects resembling those of rapamycin.
  
  
  CONCLUSIONS
  Increased resistance to tamoxifen in these MCF-7 sub-lines is not associated with hypersensitivity to PI3K inhibitors. While both drugs inhibited AKT signaling, NVP-BEZ235 resembled rapamycin in inhibiting the mTOR pathway.
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand. e.leung@auckland.ac.nz
authors.forename: Euphemia
authors.initials: E
authors.lastname: Leung
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Rewcastle
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Finlay
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Baguley
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011724:Pyridazines; D011804:Quinolines / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013629:Tamoxifen / Q000494:pharmacology*; D000096926:Benzenesulfonamides
chemical_list: D018931:Antineoplastic Agents, Hormonal; D048049:Extracellular Signal-Regulated MAP Kinases; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt; D011724:Pyridazines; D011804:Quinolines; D011960:Receptors, Estrogen; D038601:Ribosomal Protein S6; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen; C561454:omipalisib; D000096926:Benzenesulfonamides; C546842:MTOR protein, human; C531198:dactolisib