title: Lapatinib inhibits the growth of esophageal squamous cell carcinoma and synergistically interacts with 5-fluorouracil in patient-derived xenograft models.
abstract: Lapatinib is a dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2) tyrosine kinase domains. To explore the potential utility of lapatinib for the treatment of esophageal squamous cell carcinoma (ESCC), we examined the expression profiles of EGFR and HER2 in tumor tissues and in paired adjacent non-neoplastic tissues from patients with ESCC. We evaluated the antitumor effects of lapatinib alone or in combination with oxaliplatin or 5-fluorouracil (5-FU) on a panel of primary ESCC cells in vitro with various levels of EGFR and HER2 expression. The in vivo effect of lapatinib alone or in combination with oxaliplatin or 5-FU was evaluated using a primary ESCC xenograft model. EGFR was overexpressed in 80.9% (76/94) of the ESCC samples, while 24.5% (23/94) of the samples overexpressed HER2. EGFR and HER2 co-overexpression was detected in 22.3% of samples (21/94). In vitro, the primary ESCC cells were more sensitive to lapatinib combined with 5-FU or oxaliplatin than to lapatinib alone. Lapatinib in combination with 5-FU had more potent antitumor effects in the primary ESCC xenograft model, and markedly reduced the phosphorylation of EGFR and HER2, compared with lapatinib alone or in combination with oxaliplatin. These data indicate that lapatinib has activity in EGFR- and/or HER2-expressing ESCC primary cells, and that lapatinib in combination with 5-FU may be a promising treatment strategy for patients with ESCC.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, PR China.
authors.forename: Wenmin
authors.initials: W
authors.lastname: Hou
authors.forename: Xia
authors.initials: X
authors.lastname: Qin
authors.forename: Xuehua
authors.initials: X
authors.lastname: Zhu
authors.forename: Maogui
authors.initials: M
authors.lastname: Fei
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Hanlim
authors.initials: H
authors.lastname: Moon
authors.forename: Pingkuan
authors.initials: P
authors.lastname: Zhang
authors.forename: Joel
authors.initials: J
authors.lastname: Greshock
authors.forename: Kurtis E
authors.initials: KE
authors.lastname: Bachman
authors.forename: Bang-Ce
authors.initials: BC
authors.lastname: Ye
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Crystal Ying Qin
authors.initials: CY
authors.lastname: Zang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D000077341:Lapatinib; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D005472:Fluorouracil; D000077341:Lapatinib; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human