Evaluating Patient-Derived Colorectal Cancer Xenografts as Preclinical Models by Comparison with Patient Clinical Data

被引:59
作者
Nunes, Manoel [1 ,2 ]
Vrignaud, Patricia [1 ,2 ]
Vacher, Sophie [3 ]
Richon, Sophie [4 ]
Lievre, Astrid [5 ,6 ]
Cacheux, Wulfran [5 ]
Weiswald, Louis-Bastien [4 ]
Massonnet, Gerald [7 ]
Chateau-Joubert, Sophie [8 ]
Nicolas, Andre [9 ]
Dib, Colette [1 ,2 ]
Zhang, Weidong [1 ,2 ]
Watters, James [1 ,2 ]
Bergstrom, Donald [1 ,2 ]
Roman-Roman, Sergio [7 ]
Bieche, Ivan [3 ,4 ]
Dangles-Marie, Virginie [4 ,7 ]
机构
[1] Sanofi, Sanofi Oncol, Translat & Expt Med, Vitry Sur Seine, France
[2] Sanofi, Sanofi Oncol, Translat & Expt Med, Cambridge, MA USA
[3] Hop Inst Curie, Serv Genet, Paris, France
[4] Univ Paris 05, Sorbonne Paris Cite, Fac Sci Biol & Pharmaceut, IFR71, Paris, France
[5] Hop Inst Curie, Dept Oncol Med, Paris, France
[6] Univ Versailles St Quentin Yvelines, Fac Sci Biol, Versailles, France
[7] Inst Curie, Ctr Rech, Rech Translat, F-75005 Paris, France
[8] France Univ Paris Est, Ecole Natl Vet Alfort, Unit Anat Pathol, Maisons Alfort, France
[9] Hop Inst Curie, Dept Pathol, Paris, France
关键词
TUMOR XENOGRAFTS; CELL-LINES; RESISTANCE; CETUXIMAB; MUTATION; MARKER; BREAST; GENE;
D O I
10.1158/0008-5472.CAN-14-1590
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. (C) 2015 AACR.
引用
收藏
页码:1560 / 1566
页数:7
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