Combined SRC inhibitor saracatinib and anti-ErbB2 antibody H2-18 produces a synergistic antitumor effect on trastuzumab-resistant breast cancer.
Despite of the effectiveness of the anti-ErbB2 humanized antibody trastuzumab, trastuzumab resistance emerges as a major and common clinical problem. Thus, circumventing trastuzumab resistance has become an urgent need. Recently, Src inhibitor saracatinib has drawn great attention for its key role in trastuzumab response. As shown in our previous study, H2-18, an anti-ErbB2 antibody, could potently induce programmed cell death (PCD) in trastuzumab-resistant breast cancer cells. Here we combined H2-18 and a Src inhibitor, saracatinib, and studied the antitumor activity of this drug combination in trastuzumab-resistant breast cancer cell lines. The results showed that H2-18 and saracatinib could synergistically inhibit cell proliferation of BT-474, SKBR-3, HCC-1954 and HCC-1419 breast cancer cell lines in vitro. H2-18 plus saracatinib could also inhibit the HCC-1954 tumor growth more effectively in vivo than each drug alone. H2-18 plus saracatinib showed a significantly more potent PCD-inducing activity compared with either H2-18 or saracatinib alone. We conclude that enhanced PCD may contribute to the superior antitumor efficacy of this combination therapy. The combination of H2-18 and SRC inhibitor has the potential to be translated into clinic.
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, People's Republic of China.
Lingfei
L
Wang
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, People's Republic of China.
Xiaojie
X
Yu
Department of Vascular Surgery, Changhai Hospital, The Second Military Medical University, Shanghai 200433, People's Republic of China.
Jian
J
Dong
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.
Yanchun
Y
Meng
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, People's Republic of China.
Yang
Y
Yang
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, People's Republic of China.
Huajing
H
Wang
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, People's Republic of China.
Chao
C
Wang
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, People's Republic of China.
Yajun
Y
Zhang
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, People's Republic of China.
Yirong
Y
Zhao
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, People's Republic of China.
Jian
J
Zhao
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, People's Republic of China. Electronic address: hwang_smmu@163.com.
Hao
H
Wang
Department of Gastroenterology, The Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, People's Republic of China. Electronic address: lch670608@sina.com.
Cuihua
C
Lu
International Joint Cancer Institute, The Second Military Medical University, Shanghai 200433, People's Republic of China. Electronic address: bohuali1020@163.com.
Bohua
B
Li
D000818:Animals; D000906:Antibodies / Q000737:chemistry; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis; D052117:Benzodioxoles / Q000008:administration & dosage* / Q000737:chemistry; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011799:Quinazolines / Q000008:administration & dosage* / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D000068878:Trastuzumab / Q000008:administration & dosage* / Q000737:chemistry; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D000906:Antibodies; D000970:Antineoplastic Agents; D052117:Benzodioxoles; D011799:Quinazolines; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D019061:src-Family Kinases; C515233:saracatinib
Anti-ErbB2 antibody; Breast cancer; Cell death; Saracatinib; Trastuzumab resistance