ErbB-inhibitory protein: a modified ectodomain of epidermal growth factor receptor synergizes with dasatinib to inhibit growth of breast cancer cells.
Many solid tumors, including breast cancer, show increased activation of several growth factor receptors, specifically epidermal growth factor receptor (EGFR) and its family members as well as c-Src, a nonreceptor tyrosine kinase that promotes proliferation, inhibits apoptosis, and induces metastasis. We hypothesize that inhibition of c-Src and EGFRs will be an effective therapeutic strategy for triple-negative breast cancer. To test our hypothesis, we used a c-Src-specific inhibitor dasatinib (BMS-354825; Bristol-Myers Squibb) and our newly developed ErbB-inhibitory protein (EBIP), a potential pan-ErbB inhibitor, in breast cancer cells. EBIP is composed of 1 to 448 amino acids of the ectodomain of human EGFR to which the 30-amino acid epitope (known as "U" region) of rat EGFR-related protein is fused at the COOH-terminal end. The combination of dasatinib and EBIP was found to be highly effective in inhibiting the growth of four different breast cancer cells (MDA-MB-468, SKBr-3, MDA-MB-453, and MDA-MB-231) that express different levels of EGFRs. In EGFR-overexpressing MDA-MB-468 cells, the combination, but not monotherapy, markedly stimulated apoptosis mediated by caspase-9 and caspase-8 and attenuated activation of EGFR and Src as well as tyrosine kinase activity. EBIP also inhibited heregulin-induced activation of HER-2 and HER-3 in MDA-MB-453 breast cancer cells. The combination therapy was highly effective in suppressing tumor growth ( approximately 90% inhibition) in MDA-MB-468-derived xenografts in severe combined immunodeficient mice. The latter could be attributed to induction of apoptosis. We conclude that combining dasatinib and EBIP could be an effective therapeutic strategy for breast cancer by targeting EGFRs and Src signaling.
Veterans Affairs Medical Center, Detroit, Michigan 48201, USA.
Jyoti
J
Nautiyal
Yingjie
Y
Yu
Amro
A
Aboukameel
Shailender S
SS
Kanwar
Jayanta K
JK
Das
Jianhua
J
Du
Bhaumik B
BB
Patel
Fazlul H
FH
Sarkar
Arun K
AK
Rishi
Ramzi M
RM
Mohammad
Adhip P N
AP
Majumdar
D000704:Analysis of Variance; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D000069439:Dasatinib; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D066246:ErbB Receptors / Q000737:chemistry*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011993:Recombinant Fusion Proteins / Q000737:chemistry* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry* / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000069439:Dasatinib; D066246:ErbB Receptors; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D013844:Thiazoles; C552091:Ebip protein