title: Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors.
abstract: BACKGROUND
  Ovarian cancer is the major cause of death from gynaecological malignancy with a 5year survival of only ∼30% due to resistance to platinum and paclitaxel-based first line therapy. Dysregulation of the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) and RAS/extracellular signal-regulated kinase (ERK) pathways is common in ovarian cancer, providing potential new targets for 2nd line therapy.
  
  
  METHODS
  We determined the inhibition of proliferation of an extensive panel of ovarian cancer cell lines, encompassing all the major histotypes, by the dual PI3K/mTOR inhibitor PF-04691502 and a MEK inhibitor, PD-0325901. In addition, we analysed global gene expression, mutation status of key PI3K/mTOR and RAS/ERK pathway members and pathway activation to identify predictors of drug response.
  
  
  RESULTS
  PF-04691502 inhibits proliferation of the majority of cell lines with potencies that correlate with the extent of pathway inhibition. Resistant cell lines were characterised by activation of the RAS/ERK pathway as indicated by differential gene expression profiles and pathway activity analysis. PD-0325901 suppressed growth of a subset of cell lines that were characterised by high basal RAS/ERK signalling. Strikingly, using PF-04691502 and PD-0325901 in combination resulted in synergistic growth inhibition in 5/6 of PF-04691502 resistant cell lines and two cell lines resistant to both single agents showed robust synergistic growth arrest. Xenograft studies confirm the utility of combination therapy to synergistically inhibit tumour growth of PF-04691502-resistant tumours in vivo.
  
  
  CONCLUSIONS
  These studies identify dual targeted inhibitors of PI3K/mTOR in combination with inhibitors of RAS/ERK signalling as a potentially effective new approach to treating ovarian cancer.
authors.affiliation: Oncogenic Signalling and Growth Control Program, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St, Melbourne, Victoria 8006, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Sheppard
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Hannan
authors.forename: Meaghan
authors.initials: M
authors.lastname: Wall
authors.forename: Joanna
authors.initials: J
authors.lastname: Chan
authors.forename: Frances
authors.initials: F
authors.lastname: Barber
authors.forename: Jung
authors.initials: J
authors.lastname: Foo
authors.forename: Donald
authors.initials: D
authors.lastname: Cameron
authors.forename: Amelia
authors.initials: A
authors.lastname: Neilsen
authors.forename: Pui
authors.initials: P
authors.lastname: Ng
authors.forename: Jason
authors.initials: J
authors.lastname: Ellul
authors.forename: Margarete
authors.initials: M
authors.lastname: Kleinschmidt
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Kinross
authors.forename: David D
authors.initials: DD
authors.lastname: Bowtell
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Ross D
authors.initials: RD
authors.lastname: Hannan
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pearson
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004159:Diphenylamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D001549:Benzamides; D004159:Diphenylamine; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one; C506614:mirdametinib; C482128:MAP2K2 protein, human; C546842:MTOR protein, human; C482125:MAP2K1 protein, human
keywords: Ovarian cancer; PI3Kinase; RAS/ERK pathway; Therapeutics