The ErbB2-targeting antibody trastuzumab and the small-molecule SRC inhibitor saracatinib synergistically inhibit ErbB2-overexpressing gastric cancer.
The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in ErbB2-overexpressing breast and gastric cancer, but resistance to the drug is common. Here, we investigated the antitumor activity of the combination of trastuzumab and the SRC inhibitor saracatinib in ErbB2-overexpressing trastuzumab-resistant gastric cancer. The ErbB2-overexpressing human gastric cancer cell line NCI-N87 was treated with trastuzumab to obtain the trastuzumab-resistant cell line NCI-N87R. The NCI-N87R cell line showed a marked increase in SRC activity and ErbB signaling compared with the NCI-N87 cell line. Our data demonstrated that trastuzumab plus saracatinib was much more potent than either agent alone in reducing the phosphorylation of ErbB3 and AKT in both NCI-N87 and NCI-N87R gastric cancer cell lines. Trastuzumab and saracatinib synergistically inhibited the in vitro growth of NCI-N87 and NCI-N87R cell lines. Further data showed that combination therapy of trastuzumab with saracatinib resulted in a significant benefit over either agent alone in both NCI-N87 and NCI-N87R xenograft models, suggesting its potential use for treating ErbB2-overexpressing gastric cancer.
PLA General Hospital Cancer Center; PLA Postgraduate School of Medicine; Beijing, People's Republic of China; College of Pharmacy; Liaocheng University; Liaocheng, People's Republic of China.
Siqi
S
Han
School of Medicine; Nankai University; Tianjin, People's Republic of China; College of Pharmacy; Liaocheng University; Liaocheng, People's Republic of China.
Yanchun
Y
Meng
International Joint Cancer Institute; Second Military Medical University; Shanghai, People's Republic of China.
Qing
Q
Tong
School of Bioscience and Bioengineering; South China University of Technology; Guangzhou, People's Republic of China.
Guangchao
G
Li
International Joint Cancer Institute; Second Military Medical University; Shanghai, People's Republic of China.
Xunmin
X
Zhang
International Joint Cancer Institute; Second Military Medical University; Shanghai, People's Republic of China.
Yalin
Y
Chen
International Joint Cancer Institute; Second Military Medical University; Shanghai, People's Republic of China.
Shi
S
Hu
International Joint Cancer Institute; Second Military Medical University; Shanghai, People's Republic of China.
Lei
L
Zheng
Shanghai Institute of Immunology; Shanghai Jiao Tong University School of Medicine; Shanghai, People's Republic of China.
Wenlong
W
Tan
PLA General Hospital Cancer Center; PLA Postgraduate School of Medicine; Beijing, People's Republic of China.
Hui
H
Li
PLA General Hospital Cancer Center; PLA Postgraduate School of Medicine; Beijing, People's Republic of China.
Yang
Y
Chen
International Joint Cancer Institute; Second Military Medical University; Shanghai, People's Republic of China.
Ge
G
Zhang
PLA General Hospital Cancer Center; PLA Postgraduate School of Medicine; Beijing, People's Republic of China; International Joint Cancer Institute; Second Military Medical University; Shanghai, People's Republic of China; National Engineering Research Center for Antibody Medicine; Shanghai, People's Republic of China; State Key Laboratory of Antibody Medicine and Targeted Therapy; Shanghai, People's Republic of China; College of Pharmacy; Liaocheng University; Liaocheng, People's Republic of China.
Bohua
B
Li
PLA General Hospital Cancer Center; PLA Postgraduate School of Medicine; Beijing, People's Republic of China; School of Medicine; Nankai University; Tianjin, People's Republic of China; International Joint Cancer Institute; Second Military Medical University; Shanghai, People's Republic of China; School of Bioscience and Bioengineering; South China University of Technology; Guangzhou, People's Republic of China; Shanghai Institute of Immunology; Shanghai Jiao Tong University School of Medicine; Shanghai, People's Republic of China; National Engineering Research Center for Antibody Medicine; Shanghai, People's Republic of China; State Key Laboratory of Antibody Medicine and Targeted Therapy; Shanghai, People's Republic of China; College of Pharmacy; Liaocheng University; Liaocheng, People's Republic of China.
Yajun
Y
Guo
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000494:pharmacology*; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013274:Stomach Neoplasms / Q000276:immunology / Q000628:therapy*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
D061067:Antibodies, Monoclonal, Humanized; D052117:Benzodioxoles; D000081247:CSK Tyrosine-Protein Kinase; D051058:Oncogene Protein v-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab; D019061:src-Family Kinases; C515233:saracatinib; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C000631346:CSK protein, human
ErbB2; SRC; gastric cancer; saracatinib; trastuzumab