Targeting trastuzumab-resistant breast cancer cells with a lentivirus engineered to bind antibodies that recognize HER-2.
Targeting HER-2 over-expressing breast cancer cells with trastuzumab has resulted in significant improvements in both disease-free and overall survival rates. However, despite a favorable initial response, some cancer cells become resistant and develop into fatal metastatic disease. Here we report that we can specifically target HER-2 over-expressing and trastuzumab-resistant breast cancer cells by using an engineered lentivirus which has trastuzumab bound to its envelope. In vitro, this lentiviral construct mediated both the expression of reporter genes, such as enhanced green fluorescent protein (EGFP) and firefly luciferase, as well as the therapeutic gene, herpes thymidine kinase (hTK), in HER-2 over-expressing cells. Subsequent application of the pro-drug ganciclovir selectively killed breast cancer cells in which lentivirus mediated expression of hTK. In vivo, we successfully targeted the expression of firefly luciferase to trastuzumab-resistant breast cancer tumors established in nude mice. Furthermore, we found that systemic administration of trastuzumab-bound lentivirus led to expression of EGFP in circulating trastuzumab-resistant breast cancer cells. In conclusion, HER-2 over-expressing breast cancer cells resistant to trastuzumab can be targeted for selective gene expression and destruction by viruses with envelope-proteins engineered to bind to this antibody.
The Vancouver Prostate Centre, 2660 Oak Street, Vancouver, BC V6H-3Z6, Canada.
Kai-xin
KX
Zhang
Connie
C
Kim
Elaine
E
Chow
Irvin S Y
IS
Chen
William
W
Jia
Paul S
PS
Rennie
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D015774:Ganciclovir / Q000378:metabolism / Q000494:pharmacology; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009360:Neoplastic Cells, Circulating / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015774:Ganciclovir; D049452:Green Fluorescent Proteins; D008156:Luciferases; D018719:Erb-b2 Receptor Tyrosine Kinases; D013937:Thymidine Kinase; D000068878:Trastuzumab; C485184:enhanced green fluorescent protein; C508053:ERBB2 protein, human