title: Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo.
abstract: OBJECTIVE
  To evaluate the efficacy of taselisib, a selective inhibitor of PIK3CA, against primary uterine serous carcinomas (USC) harboring PIK3CA mutations and HER2/neu gene amplification.
  
  
  METHODS
  Sensitivity to taselisib was evaluated by flow-cytometry viability assays in vitro against nine primary USC cell lines. Cell cycle distribution and downstream signaling were assessed by measuring the DNA content of cells and by phosphorylation of the S6 protein by flow-cytometry. Preclinical efficacy of taselisib was also evaluated in vivo in a mouse model.
  
  
  RESULTS
  Four USC cell lines harbored HER2/neu gene amplification by FISH and two of them harbored oncogenic PIK3CA mutations. Taselisib caused a strong differential growth inhibition in both HER2/neu FISH positive and HER2/neu FISH positive/PIK3CA mutated USC cell lines when compared to lines that were FISH negative and PIK3CA wild type (taselisib IC50 mean±SEM=0.042±0.006μM in FISH+ versus 0.38±0.06μM in FISH-tumors, P<0.0001). Taselisib growth-inhibition was associated with a significant and dose-dependent increase in the percentage of cells in the G0/G1 phase of the cell cycle and dose-dependent decline in the phosphorylation of S6. Taselisib was highly active at reducing tumor growth in vivo in USC mouse xenografts harboring PIK3CA mutation and overexpressing HER2/neu (P=0.007). Mice treated with taselisib had significantly longer survival when compared to control mice (P<0.0001).
  
  
  CONCLUSIONS
  Taselisib represents a novel therapeutic option in patients harboring PIK3CA mutations and/or HER2/neu gene amplification.
authors.affiliation: Division of Gynecologic Oncology, University Campus Bio-Medico of Roma, Via Alvaro del Portillo 21, 00144 Roma, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lopez
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Carlton L
authors.initials: CL
authors.lastname: Schwab
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Emiliano
authors.initials: E
authors.lastname: Cocco
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bellone
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Bonazzoli
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Diana P
authors.initials: DP
authors.lastname: English
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Schwartz
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rutherford
authors.affiliation: Division of Gynecologic Oncology, University Campus Bio-Medico of Roma, Via Alvaro del Portillo 21, 00144 Roma, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Angioli
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, PO Box 208063, New Haven, CT 06520-8063, USA. Electronic address: alessandro.santin@yale.edu.
authors.forename: Alessandro D
authors.initials: AD
authors.lastname: Santin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D058534:Class I Phosphatidylinositol 3-Kinases; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005784:Gene Amplification; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D017404:In Situ Hybridization, Fluorescence; D066298:In Vitro Techniques; D051379:Mice; D008875:Middle Aged; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000235:genetics*; D010077:Oxazepines / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D014594:Uterine Neoplasms / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D007093:Imidazoles; D010077:Oxazepines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C582924:2-(3-(2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo(f)imidazo(1,2-d)(1,4)oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human
keywords: GDC-0032; HER2/neu; PIK3CA mutation; PIK3CA-mutant mouse; Taselisib; Uterine serous tumors