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. Mol Cancer Ther; 16(6); 1145-54. ©2017 AACR.
Highlights
Human epidermal growth factor receptor 2 (HER2; known as ERBB2) is overexpressed or amplified in approximately 15% to 20% of breast cancers, 10% to 15% of gastric cancers, and 10% to 20% of biliary tract cancers [1,2,3]
This study suggests that Src inhibition may be an effective measure to overcome trastuzumab resistance in HER2-positive cancer
Trastuzumab plus chemotherapy is the standard of care for patients with HER2-positive breast and gastric cancers
Summary
Human epidermal growth factor receptor 2 (HER2; known as ERBB2) is overexpressed or amplified in approximately 15% to 20% of breast cancers, 10% to 15% of gastric cancers, and 10% to 20% of biliary tract cancers [1,2,3]. Trastuzumab is a humanized monoclonal antibody that binds to the extracellular juxtamembrane domain of HER2 and blocks intracellular tyrosine kinase activation [4]. Trastuzumab plus chemotherapy is the standard of care for patients with HER2-positive breast and gastric cancers. Resistance to anti-HER2 therapy eventually develops as acquired or primary resistance [4]. Multiple resistance mechanisms against anti-HER2 therapy have been reported. The HER2 expression level is mainly considered as a biomarker for patient selection in clinical practice [5]
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