miRNA-150 downregulation promotes pertuzumab resistance in ovarian cancer cells via AKT activation

Arch Gynecol Obstet. 2015 Nov;292(5):1109-16. doi: 10.1007/s00404-015-3742-x. Epub 2015 May 19.


Background: Pertuzumab is a humanized mAb that binds to the extracellular region of HER2/ErbB2 and is approved for treating breast cancer. Although ovarian cancer and breast cancer have comparable levels of HER2/ErbB2 expression, clinical studies of pertuzumab in epithelial ovarian cancer patients have not met the same level of success.

Objectives: To investigate the molecular mechanisms by which pertuzumab exerts its anti-tumor effects in ovarian cancer and the mechanisms by which cancer cells achieve pertuzumab resistance.

Methods: We examined expression of miR-150 in ovarian cancer cells treated with pertuzumab or not. miR-150 knockdown impacts on pertuzumab treatment were analyzed by cell proliferation assay, apoptosis analysis and cell cycle analysis. Cell signal pathway was examined by western blot assay.

Results: Pertuzumab induced miRNA-150 expression in SKOV3 and SNU119 cells. Furthermore, suppression of miRNA-150 in both cell lines resulted in decreased drug sensitivity to pertuzumab and cell apoptosis. The blockage of G1/S checkpoint by pertuzumab was rescued as well. miRNA-150 knockdown activated PI3K-Akt pathway and LY294002 reversed the effect of miR-150 knockdown.

Conclusions: miRNA-150 downregulation may contribute to the pertuzumab resistance in ovarian cancer via, at least in part, PI3K-akt pathway.

Keywords: Drug resistance; Ovarian cancer; Pertuzumab; miR-150.

MeSH terms

  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy
  • Carcinoma, Ovarian Epithelial
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Chromones
  • Down-Regulation
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • MicroRNAs / genetics*
  • Morpholines
  • Neoplasms, Glandular and Epithelial / metabolism
  • Neoplasms, Glandular and Epithelial / pathology
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, ErbB-2
  • Signal Transduction / drug effects*


  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Chromones
  • MicroRNAs
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Proto-Oncogene Proteins c-akt
  • pertuzumab