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Resistance Mechanism against Trastuzumab in HER2-Positive Cancer Cells and Its Negation by Src Inhibition

Cited 28 time in Web of Science Cited 28 time in Scopus
Authors
Jin, Mei Hua; Nam, Ah-Rong; Park, Ji Eun; Bang, Ju-Hee; Bang, Yung-Jue; Oh, Do-Youn
Issue Date
2017-06
Citation
Molecular Cancer Therapeutics, Vol.16 No.6, pp.1145-1154
Abstract
Trastuzumab in combination with chemotherapy is the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancers. Several resistance mechanisms against anti-HER2 therapy have been proposed. Src activation has been suggested to be responsible for the resistance of HER2-positive breast cancer. In our study, we generated four trastuzumab-resistant (HR) cancer cell lines from HER2-amplified gastric and biliary tract cancer cell lines (SNU-216, NCI-N87, SNU-2670, and SNU-2773). Elevated Src phosphorylation was detected in SNU2670HR and NCI-N87HR cell lines, but not in SNU216HR or SNU2773HR cell lines. In SNU216HR and SNU2773HR cell lines, phospho-FAK (focal adhesion kinase) was elevated. Bosutinib as a Src inhibitor suppressed growth, cell-cycle progression, and migration in both parental and HR cell lines. Specifically, Src interacted with FAK to affect downstream molecules such as AKT, ERK, and STAT3. Bosutinib showed more potent antitumor effects in Src-activated HR cell lines than parental cell lines. Taken together, this study suggests that Src inhibition may be an effective measure to overcome trastuzumab resistance in HER2-positive cancer. (C) 2017 AACR.
ISSN
1535-7163
URI
https://hdl.handle.net/10371/173132
DOI
https://doi.org/10.1158/1535-7163.MCT-16-0669
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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