Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2-extracellular domain in human cancer cells

Ryosuke Yoshida, Hiroshi Tazawa, Yuuri Hashimoto, Shuuya Yano, Teppei Onishi, Tsuyoshi Sasaki, Yasuhiro Shirakawa, Hiroyuki Kishimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic eYcacy against HER2-positive breast and gastric cancers; however, acquired resistance presents a formidable obstacle to longterm tumor responses in the majority of patients. Here, we show the mechanism of resistance to trastuzumab in HER2- positive human cancer cells and explore the molecular sensitization by exogenous expression of HER2-extracellular domain (ECD) in HER2-negative or trastuzumab-resistant human cancer cells. We found that long-term exposure to trastuzumab induced resistance in HER2-positive cancer cells; HER2 expression was downregulated, and antibodydependent cellular cytotoxicity (ADCC) activity was impaired. We next examined the hypothesis that trastuzumab- resistant cells could be re-sensitized by the transfer of non-functional HER2-ECD. Exogenous HER2-ECD expression induced by the stable transfection of a plasmid vector or infection with a replication-deWcient adenovirus vector had no apparent eVect on the signaling pathway, but strongly enhanced ADCC activity in low HER2-expressing or trastuzumab-resistant human cancer cells. Our data indicate that restoration of HER2-ECD expression sensitizes HER2-negative or HER2-downregulated human cancer cells to trastuzumab-mediated ADCC, an outcome that has important implications for the treatment of human cancers.

Original languageEnglish
Pages (from-to)1905-1916
Number of pages12
JournalCancer Immunology, Immunotherapy
Volume61
Issue number11
DOIs
Publication statusPublished - Nov 2012

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Keywords

  • ADCC
  • Adenovirus
  • Extracellular domain
  • HER2
  • Trastuzumab

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy

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