title: Lapatinib and 17AAG reduce 89Zr-trastuzumab-F(ab')2 uptake in SKBR3 tumor xenografts.
abstract: Human epidermal growth factor receptor-2 (HER2) directed therapy potentially can be improved by insight in drug effects on HER2 expression. This study evaluates the effects of the EGFR/HER2 tyrosine kinase inhibitor lapatinib, the heat shock protein-90 inhibitor 17AAG, and their combination, on HER2 expression with in vivo HER2-PET imaging. Lapatinib and 17AAG effects on EGFR and HER2 membrane expression were determined in vitro using flow cytometry of human SKBR3 tumor cells. Effect of lapatinib on HER2 internalization was studied in vitro by (89)Zr-trastuzumab-F(ab')(2) internalization. For in vivo evaluation, (89)Zr-trastuzumab-F(ab')(2) μPET imaging was performed two times with a 7 day interval. Lapatinib was administered for 6 days, starting 1 day after the baseline scan. 17AAG was given 1 day before the second (89)Zr-trastuzumab-F(ab')(2) injection. Imaging data were compared with ex vivo biodistribution analysis and HER2 immunohistochemical staining. 17AAG treatment lowered EGFR expression by 41% (P = 0.016) and HER2 by 76% (P = 0.022). EGFR/HER2 downregulation by 17AAG was inhibited by lapatinib pretreatment. Lapatinib reduced internalization of (89)Zr-trastuzumab-F(ab')(2) with 25% (P = 0.0022). (89)Zr-trastuzumab-F(ab')(2) tumor to blood ratio was lowered 32% by lapatinib (P = 0.00004), 34% by 17AAG (P = 0.0022) and even 53% by the combination (P = 0.011). Lapatinib inhibits HER2 internalization and 17AAG lowers HER2 membrane expression. Both drugs reduce (89)Zr-trastuzumab-F(ab')(2) tumor uptake. Based on our findings, supported by previous preclinical data indicating the antitumor potency of lapatinib in combination with HSP90 inhibition, combination of these drugs deserves further investigation.
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Thijs H
authors.initials: TH
authors.lastname: Oude Munnink
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: Silke R
authors.initials: SR
authors.lastname: Vedelaar
authors.forename: Hetty
authors.initials: H
authors.lastname: Timmer-Bosscha
authors.forename: Carolina P
authors.initials: CP
authors.lastname: Schröder
authors.forename: Adrienne H
authors.initials: AH
authors.lastname: Brouwers
authors.forename: Marjolijn N
authors.initials: MN
authors.lastname: Lub-de Hooge
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D016227:Benzoquinones / Q000627:therapeutic use*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018773:Genes, erbB-1; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism*; D047029:Lactams, Macrocyclic / Q000627:therapeutic use*; D000077341:Lapatinib; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011799:Quinazolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D007140:Immunoglobulin Fab Fragments; D047029:Lactams, Macrocyclic; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C571668:zirconium-89-trastuzumab; C112765:tanespimycin