title: EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype.
abstract: Muscle-invasive bladder carcinoma (MIBC) constitutes a heterogeneous group of tumors with a poor outcome. Molecular stratification of MIBC may identify clinically relevant tumor subgroups and help to provide effective targeted therapies. From seven series of large-scale transcriptomic data (383 tumors), we identified an MIBC subgroup accounting for 23.5% of MIBC, associated with shorter survival and displaying a basal-like phenotype, as shown by the expression of epithelial basal cell markers. Basal-like tumors presented an activation of the epidermal growth factor receptor (EGFR) pathway linked to frequent EGFR gains and activation of an EGFR autocrine loop. We used a 40-gene expression classifier derived from human tumors to identify human bladder cancer cell lines and a chemically induced mouse model of bladder cancer corresponding to human basal-like bladder cancer. We showed, in both models, that tumor cells were sensitive to anti-EGFR therapy. Our findings provide preclinical proof of concept that anti-EGFR therapy can be used to target a subset of particularly aggressive MIBC tumors expressing basal cell markers and provide diagnostic tools for identifying these tumors.
authors.affiliation: CNRS, UMR 144, Institut Curie, 75005 Paris, France. Institut Curie, Centre de Recherche, 75005 Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rebouissou
authors.affiliation: CNRS, UMR 144, Institut Curie, 75005 Paris, France. Institut Curie, Centre de Recherche, 75005 Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bernard-Pierrot
authors.affiliation: Ligue Nationale Contre le Cancer, Cartes d'Identité des Tumeurs Program, 75013 Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reyniès
authors.affiliation: CNRS, UMR 144, Institut Curie, 75005 Paris, France. Institut Curie, Centre de Recherche, 75005 Paris, France.
authors.forename: May-Linda
authors.initials: ML
authors.lastname: Lepage
authors.affiliation: CNRS, UMR 144, Institut Curie, 75005 Paris, France. Institut Curie, Centre de Recherche, 75005 Paris, France.
authors.forename: Clémentine
authors.initials: C
authors.lastname: Krucker
authors.affiliation: CNRS, UMR 144, Institut Curie, 75005 Paris, France. Institut Curie, Centre de Recherche, 75005 Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Chapeaublanc
authors.affiliation: CNRS, UMR 144, Institut Curie, 75005 Paris, France. Institut Curie, Centre de Recherche, 75005 Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Hérault
authors.affiliation: CNRS, UMR 144, Institut Curie, 75005 Paris, France. Institut Curie, Centre de Recherche, 75005 Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Kamoun
authors.affiliation: CNRS, UMR 144, Institut Curie, 75005 Paris, France. Institut Curie, Centre de Recherche, 75005 Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Caillault
authors.affiliation: Ligue Nationale Contre le Cancer, Cartes d'Identité des Tumeurs Program, 75013 Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Letouzé
authors.affiliation: Ligue Nationale Contre le Cancer, Cartes d'Identité des Tumeurs Program, 75013 Paris, France.
authors.forename: Nabila
authors.initials: N
authors.lastname: Elarouci
authors.affiliation: Service d'Urologie, Hôpital Foch, 92150 Suresnes, France. Université de Versailles, Saint-Quentin-en-Yvelines, Faculté de Médecine Paris, Ile-de-France Ouest, 78280 Guyancourt, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Neuzillet
authors.affiliation: Département de Pathologie, Hôpital Foch, 92150 Suresnes, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Denoux
authors.affiliation: Service d'Anatomie Pathologique, Hôpital Saint Joseph, 75014 Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Molinié
authors.affiliation: AP-HP, Hôpitaux Universitaires Henri Mondor, Service d'Urologie, 94000 Créteil, France.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Vordos
authors.affiliation: Département de Biostatistique et d'Epidémiologie, Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Laplanche
authors.affiliation: AP-HP, Hôpitaux Universitaires Henri Mondor, Département de Pathologie, 94000 Créteil, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Maillé
authors.affiliation: INSERM, Unité 955, 94000 Créteil, France. Université Paris-Est, Faculté de Médecine, 94000 Créteil, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Soyeux
authors.affiliation: INSERM, Unité 955, 94000 Créteil, France. Université Paris-Est, Faculté de Médecine, 94000 Créteil, France.
authors.forename: Karina
authors.initials: K
authors.lastname: Ofualuka
authors.affiliation: CNRS, UMR 144, Institut Curie, 75005 Paris, France. Institut Curie, Centre de Recherche, 75005 Paris, France. Institut Curie, Département de Chirurgie, 75005 Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Reyal
authors.affiliation: CNRS, UMR 144, Institut Curie, 75005 Paris, France. Institut Curie, Centre de Recherche, 75005 Paris, France. INSERM, U900, Institut Curie, 75005 Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Biton
authors.affiliation: AP-HP, Hôpital Cochin, Département de Pathologie, 75014 Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Sibony
authors.affiliation: INSERM, U900, Institut Curie, 75005 Paris, France. Service de Biostatistique, Institut Curie, 75005 Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Paoletti
authors.affiliation: Jack Birch Unit of Molecular Carcinogenesis, Department of Biology, University of York, York Y010 5DD, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Southgate
authors.affiliation: CNRS, UMR 8200, Institut de Cancérologie Gustave Roussy, 94805 Villejuif, France. INSERM, U946, 75010 Paris, France.
authors.forename: Simone
authors.initials: S
authors.lastname: Benhamou
authors.affiliation: Service d'Urologie, Hôpital Foch, 92150 Suresnes, France. Université de Versailles, Saint-Quentin-en-Yvelines, Faculté de Médecine Paris, Ile-de-France Ouest, 78280 Guyancourt, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lebret
authors.affiliation: AP-HP, Hôpitaux Universitaires Henri Mondor, Département de Pathologie, 94000 Créteil, France. INSERM, Unité 955, 94000 Créteil, France. Université Paris-Est, Faculté de Médecine, 94000 Créteil, France. AP-HP, Hôpitaux Universitaires Henri Mondor, Plateforme de Ressources Biologiques, 94000 Créteil, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Allory
authors.affiliation: CNRS, UMR 144, Institut Curie, 75005 Paris, France. Institut Curie, Centre de Recherche, 75005 Paris, France. francois.radvanyi@curie.fr.
authors.forename: François
authors.initials: F
authors.lastname: Radvanyi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D002085:Butylhydroxybutylnitrosamine; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006801:Humans; D007633:Keratins / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009132:Muscles / Q000187:drug effects / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D059467:Transcriptome / Q000235:genetics; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy*
chemical_list: C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D047428:Protein Kinase Inhibitors; D002085:Butylhydroxybutylnitrosamine; D007633:Keratins; D066246:ErbB Receptors