title: Antitumor activity of a combination of dual PI3K/mTOR inhibitor SAR245409 and selective MEK1/2 inhibitor pimasertib in endometrial carcinomas.
abstract: OBJECTIVE
  We aimed to clarify whether dual inhibition of PI3K/MAPK and MAPK pathways synergistically suppresses cell growth in endometrial cancer cells.
  
  
  METHODS
  We exposed a panel of 12 endometrial cancer cell lines to a PI3K/mTOR inhibitor (voxtalisib, SAR245409) and/or a MEK inhibitor (pimasertib). The effect of each drug singly or in combination was evaluated by MTT assay, flow cytometry, and immunoblotting. Combination indexes (CIs) were calculated using the Chou-Talalay method to evaluate the synergy.
  
  
  RESULTS
  The IC50 values for SAR245409 and pimasertib varied from 0.5 μM to 7 μM and from 0.1 μM to >20 μM, respectively. A combination of both compounds (1 μM SAR245409 and 30 nM pimasertib) caused a synergistic antitumor effect in 6 out of 12 endometrial cell lines (CI, 0.07-0.46). The synergistic effect was exclusively observed in 6 pimasertib-sensitive cell lines (IC50 of pimasertib, ≤5 μM). We found that 30 nM pimasertib, a concentration much lower than the IC50 for each cell line, was sufficient to cause a synergistic effect with SAR245409. Flow cytometric analysis showed that this combination significantly increased the population of G1 cells. However, a combination of rapamycin (an mTOR inhibitor) and pimasertib did not induce a synergistic effect in endometrial cancer cells, except for HEC-1B cells.
  
  
  CONCLUSIONS
  The combination of a PI3K/mTOR inhibitor and a MEK inhibitor induced a synergistic antitumor effect in certain endometrial cancer cells. This study underscores the importance of using optimized doses of antitumor agents, singly or in combination, in treating endometrial cancer.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Inaba
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan. Electronic address: katsutoshi-tky@umin.ac.jp.
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Oda
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
authors.forename: Kenbun
authors.initials: K
authors.lastname: Sone
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Miyasaka
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kashiyama
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Uehara
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Arimoto
authors.affiliation: Kanagawa Health Service Association, Kanagawa, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuramoto
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Wada-Hiraike
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Kawana
authors.affiliation: Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yano
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Osuga
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujii
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: C550600:N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; C576808:XL765; D009536:Niacinamide; C482128:MAP2K2 protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human
keywords: Endometrial carcinoma; MAPK; MEK; Molecular target therapy; PI3K/mTOR