title: ErbBs inhibition by lapatinib blocks tumor growth in an orthotopic model of human testicular germ cell tumor.
abstract: In this work, we have analyzed the expression of different members of the ErbB family in human samples of testicular germ cell tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expression was maintained when primary tumors were orthotopically implanted in nude mice. We have chosen a choriocarcinoma model characterized by high levels of ErbB1, but also of ErbB2 and ErbB3, to assay the in vivo effect of ErbB inhibitors on tumoral growth. Our results showed a complete lack of effect (refractoriness) to the pure ErbB1 receptor inhibitors cetuximab and gefitinib. While these inhibitors blocked ErbB1 phosphorylation, ErbB2 phosphorylation was not affected, suggesting an ErbB1-independent activation of this receptor. To confirm the importance of ErbB2 activation, animals were treated with lapatinib, a dual ErbB1 and ErbB2 inhibitor. Lapatinib treatment caused a 50% inhibition in tumor growth, an effect correlated with a blockade of both ErbB1 and ErbB2 phosphorylation levels, and of downstream signaling pathways (Akt, ERKs and Stat3). ErbB2 activation could still occur due to the formation of ErbB2/ErbB3 heterodimers, and ErbB3 activation was completely inhibited by lapatinib. Finally, combined inhibition of ErbB1 (gefitinib) and ErbB3 activities (knockdown expression by shRNA) inhibited tumoral testicular cells proliferation in a similar way to lapatinib. Our results explain why lapatinib but not anti-ErbB1 agents might be effective for treatment of testicular GCT patients.
authors.affiliation: Laboratori de Recerca Translacional, Institut Català d'Oncologia, Hospital Duran i Reynals, 08908 L'Hospitalet de Llobregat (Barcelona), Spain.
authors.forename: M
authors.initials: M
authors.lastname: Juliachs
authors.forename: W
authors.initials: W
authors.lastname: Castillo-Ávila
authors.forename: A
authors.initials: A
authors.lastname: Vidal
authors.forename: J M
authors.initials: JM
authors.lastname: Piulats
authors.forename: X
authors.initials: X
authors.lastname: Garcia Del Muro
authors.forename: E
authors.initials: E
authors.lastname: Condom
authors.forename: J
authors.initials: J
authors.lastname: Hernández-Losa
authors.forename: C
authors.initials: C
authors.lastname: Teixidó
authors.forename: A
authors.initials: A
authors.lastname: Pandiella
authors.forename: M
authors.initials: M
authors.lastname: Graupera
authors.forename: O
authors.initials: O
authors.lastname: Casanovas
authors.forename: J R
authors.initials: JR
authors.lastname: Germà
authors.forename: A
authors.initials: A
authors.lastname: Villanueva
authors.forename: F
authors.initials: F
authors.lastname: Viñals
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D018236:Carcinoma, Embryonal / Q000188:drug therapy / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab; D002822:Choriocarcinoma / Q000188:drug therapy / Q000378:metabolism; D018240:Endodermal Sinus Tumor / Q000188:drug therapy / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047468:Immunoprecipitation; D000077341:Lapatinib; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors; D018243:Teratocarcinoma / Q000188:drug therapy / Q000378:metabolism; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068818:Cetuximab; D066246:ErbB Receptors; D000077156:Gefitinib; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human