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

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17 Citations (Scopus)


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
Issue number11
Publication statusPublished - Nov 2012



  • ADCC
  • Adenovirus
  • Extracellular domain
  • HER2
  • Trastuzumab

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy

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