RT Journal Article
SR Electronic
T1 Resistance Mechanism against Trastuzumab in HER2-Positive Cancer Cells and Its Negation by Src Inhibition
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 1145
OP 1154
DO 10.1158/1535-7163.MCT-16-0669
VO 16
IS 6
A1 Jin, Mei Hua
A1 Nam, Ah-Rong
A1 Park, Ji Eun
A1 Bang, Ju-Hee
A1 Bang, Yung-Jue
A1 Oh, Do-Youn
YR 2017
UL http://mct.aacrjournals.org/content/16/6/1145.abstract
AB 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.