title: Evaluating patient-derived colorectal cancer xenografts as preclinical models by comparison with patient clinical data.
abstract: Development of targeted therapeutics required translationally relevant preclinical models with well-characterized cancer genome alterations. Here, by studying 52 colorectal patient-derived tumor xenografts (PDX), we examined key molecular alterations of the IGF2-PI3K and ERBB-RAS pathways and response to cetuximab. PDX molecular data were compared with that published for patient colorectal tumors in The Cancer Genome Atlas. We demonstrated a significant pattern of mutual exclusivity of genomic abnormalities in the IGF2-PI3K and ERBB-RAS pathways. The genomic anomaly frequencies observed in microsatellite stable PDX reproduce those detected in nonhypermutated patient tumors. We found frequent IGF2 upregulation (16%), which was mutually exclusive with IRS2, PIK3CA, PTEN, and INPP4B alterations, supporting IGF2 as a potential drug target. In addition to maintaining the genomic and histologic diversity, correct preclinical models need to reproduce drug response observed in patients. Responses of PDXs to cetuximab recapitulate also clinical data in patients, with partial or complete response in 15% (8 of 52) of PDXs and response strictly restricted to KRAS wild-type models. The response rate reaches 53% (8 of 15) when KRAS, BRAF, and NRAS mutations are concomitantly excluded, proving a functional cross-validation of predictive biomarkers obtained retrospectively in patients. Collectively, these results show that, because of their clinical relevance, colorectal PDXs are appropriate tools to identify both new targets, like IGF2, and predictive biomarkers of response/resistance to targeted therapies.
authors.affiliation: Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Vitry-sur-Seine, France. Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Cambridge, Massachusetts.
authors.forename: Manoel
authors.initials: M
authors.lastname: Nunes
authors.affiliation: Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Vitry-sur-Seine, France. Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Cambridge, Massachusetts.
authors.forename: Patricia
authors.initials: P
authors.lastname: Vrignaud
authors.affiliation: Service de Génétique, Hôpital Institut Curie, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vacher
authors.affiliation: IFR71, Faculté de Sciences Biologiques et Pharmaceutiques, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Richon
authors.affiliation: Département d'Oncologie médicale, Hôpital Institut Curie, Paris, France. Université de Versailles Saint-Quentin en Yvelines, Faculté des Sciences Biologiques, Versailles, France.
authors.forename: Astrid
authors.initials: A
authors.lastname: Lièvre
authors.affiliation: Département d'Oncologie médicale, Hôpital Institut Curie, Paris, France.
authors.forename: Wulfran
authors.initials: W
authors.lastname: Cacheux
authors.affiliation: IFR71, Faculté de Sciences Biologiques et Pharmaceutiques, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Louis-Bastien
authors.initials: LB
authors.lastname: Weiswald
authors.affiliation: Recherche Translationnelle, Centre de Recherche, Institut Curie, Paris, France.
authors.forename: Gerald
authors.initials: G
authors.lastname: Massonnet
authors.affiliation: France Université Paris-Est, Ecole Nationale Vétérinaire d'Alfort, Unité d'Anatomie Pathologique, Maisons-Alfort, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Chateau-Joubert
authors.affiliation: Département de Pathologie, Hôpital Institut Curie, Paris, France.
authors.forename: André
authors.initials: A
authors.lastname: Nicolas
authors.affiliation: Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Vitry-sur-Seine, France. Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Cambridge, Massachusetts.
authors.forename: Colette
authors.initials: C
authors.lastname: Dib
authors.affiliation: Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Vitry-sur-Seine, France. Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Cambridge, Massachusetts.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Vitry-sur-Seine, France. Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Cambridge, Massachusetts.
authors.forename: James
authors.initials: J
authors.lastname: Watters
authors.affiliation: Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Vitry-sur-Seine, France. Translational and Experimental Medicine, Sanofi Oncology, Sanofi, Cambridge, Massachusetts.
authors.forename: Donald
authors.initials: D
authors.lastname: Bergstrom
authors.affiliation: Recherche Translationnelle, Centre de Recherche, Institut Curie, Paris, France.
authors.forename: Sergio
authors.initials: S
authors.lastname: Roman-Roman
authors.affiliation: Service de Génétique, Hôpital Institut Curie, Paris, France. IFR71, Faculté de Sciences Biologiques et Pharmaceutiques, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: IFR71, Faculté de Sciences Biologiques et Pharmaceutiques, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Recherche Translationnelle, Centre de Recherche, Institut Curie, Paris, France. virginie.dangles-marie@curie.fr.
authors.forename: Virginie
authors.initials: V
authors.lastname: Dangles-Marie
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D055028:Comparative Genomic Hybridization / Q000379:methods; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts / Q000378:metabolism / Q000473:pathology*; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D018739:Oncogene Proteins v-erbB / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D018739:Oncogene Proteins v-erbB; D016283:Proto-Oncogene Proteins p21(ras)