Oncogenic PIK3CA gene mutations and HER2/neu gene amplifications determine the sensitivity of uterine serous carcinoma cell lines to GDC-0980, a selective inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2)

Am J Obstet Gynecol. 2013 Nov;209(5):465.e1-9. doi: 10.1016/j.ajog.2013.07.020. Epub 2013 Jul 24.

Abstract

Objective: To evaluate PIK3CA mutational status and c-erbB2 gene amplification in a series of primary uterine serous carcinomas (USC) cell lines. To assess the efficacy of GDC-0980, a potent inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2), against primary USC harboring HER2/neu gene amplification and/or PIK3CA mutations.

Study design: Twenty-two primary USC cell lines were evaluated for c-erbB2 oncogene amplification by fluorescence in situ hybridization (FISH) assays and for PIK3CA gene mutations by direct DNA sequencing of exons 9 and 20. In vitro sensitivity to GDC-0980 was evaluated by flow-cytometry-based viability and proliferation assays. Downstream cellular responses to GDC-0980 were assessed by measuring phosphorylation of the 4-EBP1 protein by flow-cytometry.

Results: Five of 22 (22.7%) USC cell lines contained oncogenic PIK3CA mutations although 9 (40.9%) harbored c-erbB2 gene amplification by FISH. GDC-0980 caused a strong differential growth inhibition in FISH+ USC when compared with FISH- (GDC-0980 IC50 mean ± SEM = 0.29 ± 0.05 μM in FISH+ vs 1.09 ± 0.20 μM in FISH- tumors, P = .02). FISH+ USC harboring PIK3CA mutations were significantly more sensitive to GDC-0980 exposure when compared with USC cell lines harboring wild-type PIK3CA (P = .03). GDC-0980 growth-inhibition was associated with a significant and dose-dependent decline in phosphorylated 4-EBP1 levels.

Conclusion: Oncogenic PIK3CA mutations and c-erbB2 gene amplification may represent biomarkers to identify patients harboring USC who may benefit most from the use of GDC-0980.

Keywords: GDC-0980; HER2/neu; PIK3CA; endometrial neoplasms; mTOR inhibitor; uterine serous tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use*
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
  • Carcinoma, Papillary / drug therapy
  • Carcinoma, Papillary / genetics*
  • Cell Line, Tumor
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Drug Resistance, Neoplasm / genetics
  • Endometrial Neoplasms / drug therapy
  • Endometrial Neoplasms / genetics*
  • Female
  • Gene Amplification / genetics
  • Genes, erbB-2 / genetics*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Middle Aged
  • Mutation
  • Phosphatidylinositol 3-Kinases / genetics*
  • Pyrimidines / therapeutic use*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*

Substances

  • 1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Pyrimidines
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • TOR Serine-Threonine Kinases