The ErbB2-targeting antibody trastuzumab and the small-molecule SRC inhibitor saracatinib synergistically inhibit ErbB2-overexpressing gastric cancer

MAbs. Mar-Apr 2014;6(2):403-8. doi: 10.4161/mabs.27443. Epub 2013 Dec 9.

Abstract

The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in ErbB2-overexpressing breast and gastric cancer, but resistance to the drug is common. Here, we investigated the antitumor activity of the combination of trastuzumab and the SRC inhibitor saracatinib in ErbB2-overexpressing trastuzumab-resistant gastric cancer. The ErbB2-overexpressing human gastric cancer cell line NCI-N87 was treated with trastuzumab to obtain the trastuzumab-resistant cell line NCI-N87R. The NCI-N87R cell line showed a marked increase in SRC activity and ErbB signaling compared with the NCI-N87 cell line. Our data demonstrated that trastuzumab plus saracatinib was much more potent than either agent alone in reducing the phosphorylation of ErbB3 and AKT in both NCI-N87 and NCI-N87R gastric cancer cell lines. Trastuzumab and saracatinib synergistically inhibited the in vitro growth of NCI-N87 and NCI-N87R cell lines. Further data showed that combination therapy of trastuzumab with saracatinib resulted in a significant benefit over either agent alone in both NCI-N87 and NCI-N87R xenograft models, suggesting its potential use for treating ErbB2-overexpressing gastric cancer.

Keywords: ErbB2; SRC; gastric cancer; saracatinib; trastuzumab.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzodioxoles / pharmacology*
  • CSK Tyrosine-Protein Kinase
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Drug Synergism
  • Humans
  • Immunotherapy / methods*
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation / genetics
  • Oncogene Protein v-akt / metabolism
  • Quinazolines / pharmacology*
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / immunology
  • Receptor, ErbB-2 / metabolism
  • Receptor, ErbB-3 / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Stomach Neoplasms / immunology
  • Stomach Neoplasms / therapy*
  • Trastuzumab
  • Xenograft Model Antitumor Assays
  • src-Family Kinases / antagonists & inhibitors*
  • src-Family Kinases / biosynthesis
  • src-Family Kinases / genetics

Substances

  • Antibodies, Monoclonal, Humanized
  • Benzodioxoles
  • Quinazolines
  • saracatinib
  • ERBB2 protein, human
  • ERBB3 protein, human
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • CSK Tyrosine-Protein Kinase
  • src-Family Kinases
  • CSK protein, human
  • Oncogene Protein v-akt
  • Trastuzumab