title: Impact of ERBB2 mutations on in vitro sensitivity of bladder cancer to lapatinib.
abstract: Lapatinib, a dual tyrosine kinase inhibitor of ErbB1 and ErbB2, shows a clinical benefit in a subset of patients with advanced urothelial bladder cancer (UBC). We hypothesized that the corresponding gene, ERBB2, is affected by mutations in a subset of UBC and that these mutations impact ErbB2 function, signaling, UBC proliferation, gene expression, and predict response to lapatinib. We found ERBB2 mutations in 5 of 33 UBC cell lines (15%), all of which were derived from invasive or high grade tumors. Phosphorylation and activation of ErbB2 and its downstream pathways were markedly enhanced in mutated cell lines compared with the ERBB2 wild-type. In addition, the gene expression profile was distinct, specifically for genes encoding for proteins of the extracellular matrix. RT112 cells infected with ERBB2 mutants showed a particular growth pattern ("mini-foci"). Upon treatment with lapatinib, 93% of these "mini-foci" were reversed. The sensitivity to lapatinib was greatest among cell lines with ERBB2 mutations. In conclusion, ERBB2 mutations occur in a subset of UBC and impact proliferation, signaling, gene expression and predict a greater response to lapatinib. If confirmed in the clinical setting, this may lead the way toward personalized treatment of a subset of UBC.
authors: Department of Urology; Comprehensive Cancer Center; Medical University and General Hospital Vienna; Vienna, Austria.
authors: Michela
authors: M
authors: de Martino
authors: Department of Urology; Weill Cornell Medical College; New York Presbyterian Hospital; New York, NY USA.
authors: Dazhong
authors: D
authors: Zhuang
authors: Department of Urology; Comprehensive Cancer Center; Medical University and General Hospital Vienna; Vienna, Austria.
authors: Tobias
authors: T
authors: Klatte
authors: Department of Urology; Weill Cornell Medical College; New York Presbyterian Hospital; New York, NY USA.
authors: Malte
authors: M
authors: Rieken
authors: Institut Universitaire de Cancérologie; GRC-05; ONCOTYPE-Uro; Université Paris 6; Paris, France; Academic Department of Urology; Pitié-Salpétrière Hospital; Paris, France.
authors: Morgan
authors: M
authors: Rouprêt
authors: Department of Urology; Weill Cornell Medical College; New York Presbyterian Hospital; New York, NY USA.
authors: Evanguelos
authors: E
authors: Xylinas
authors: Department of Medicine; Weill Cornell Medical College; New York Presbyterian Hospital; New York, NY USA.
authors: Thomas
authors: T
authors: Clozel
authors: Genome Sciences Center; Vancouver, BC Canada.
authors: Martin
authors: M
authors: Krzywinski
authors: Department of Physiology and Biophysics; Weill Cornell Medical College; New York Presbyterian Hospital; New York, NY USA.
authors: Olivier
authors: O
authors: Elemento
authors: Department of Urology; Comprehensive Cancer Center; Medical University and General Hospital Vienna; Vienna, Austria; Department of Urology; Weill Cornell Medical College; New York Presbyterian Hospital; New York, NY USA; Department of Urology; UT Southwestern; Dallas, TX USA.
authors: Shahrokh F
authors: SF
authors: Shariat
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D000077341:Lapatinib; D009154:Mutation; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: ERBB2; bladder cancer; epidermal growth factor; lapatinib; personalized medicine