A Molecularly Annotated Platform of Patient-Derived Xenografts (“Xenopatients”) Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer

Cancer Discovery - Tập 1 Số 6 - Trang 508-523 - 2011
Andrea Bertotti1, Giorgia Migliardi1, Francesco Galimi1, Francesco Sassi1, Davide Torti1, Claudio Isella1, Davide Corà1, Federica Di Nicolantonio1, Michela Buscarino1, Consalvo Petti1, Dario Ribero1, Nadia Russolillo1, Andrea Muratore1, Paolo Massucco1, Alberto Pisacane1, Luca Molinaro1, Emanuele Valtorta1, Andrea Sartore‐Bianchi1, Mauro Risio1, Lorenzo Capussotti1, Gabriella Fontanini1, Salvatore Siena1, Enzo Médico1, Anna Sapino1, Silvia Marsoni1, Paolo M. Comoglio1, Alberto Bardelli1, Livio Trusolino1
1Authors' Affiliations: 1Laboratory of Molecular Pharmacology, 2Laboratory of Oncogenomics, 3Laboratory of Systems Biology, 4Laboratory of Molecular Genetics, 5Division of Surgical Oncology, 6Unit of Pathology, 7Clinical Coordination Unit, and 8Molecular Clinical Oncology, Institute for Cancer Research and Treatment, Torino; Departments of 9Oncological Sciences and 10Biomedical Sciences and Human Oncology, University of Torino Medical School, Torino; 11Department of Surgery, Mauriziano Umberto I Hospital, Torino; 12FIRC Institute of Molecular Oncology, Milano; 13Division of Pathology, 14Falck Division of Medical Oncology, Ospedale Niguarda Ca' Granda, Milano; and 15Southern Europe New Drug Organization Foundation, Milano, Italy

Tóm tắt

Abstract Only a fraction of patients with metastatic colorectal cancer receive clinical benefit from therapy with anti-epidermal growth factor receptor (EGFR) antibodies, which calls for the identification of novel biomarkers for better personalized medicine. We produced large xenograft cohorts from 85 patient-derived, genetically characterized metastatic colorectal cancer samples (“xenopatients”) to discover novel determinants of therapeutic response and new oncoprotein targets. Serially passaged tumors retained the morphologic and genomic features of their original counterparts. A validation trial confirmed the robustness of this approach: xenopatients responded to the anti-EGFR antibody cetuximab with rates and extents analogous to those observed in the clinic and could be prospectively stratified as responders or nonresponders on the basis of several predictive biomarkers. Genotype–response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. Importantly, HER2 amplification was also enriched in clinically nonresponsive KRAS wild-type patients. A proof-of-concept, multiarm study in HER2-amplified xenopatients revealed that the combined inhibition of HER2 and EGFR induced overt, long-lasting tumor regression. Our results suggest promising therapeutic opportunities in cetuximab-resistant patients with metastatic colorectal cancer, whose medical treatment in the chemorefractory setting remains an unmet clinical need. Significance: Direct transfer xenografts of tumor surgical specimens conserve the interindividual diversity and the genetic heterogeneity typical of the tumors of origin, combining the flexibility of preclinical analysis with the informative value of population-based studies. Our suite of patient-derived xenografts from metastatic colorectal carcinomas reliably mimicked disease response in humans, prospectively recapitulated biomarker-based case stratification, and identified HER2 as a predictor of resistance to anti-epidermal growth factor receptor antibodies and of response to combination therapies against HER2 and epidermal growth factor receptor in this tumor setting. Cancer Discovery; 1(6); 508–23. ©2011 AACR. Read the Commentary on this article by Ciardiello and Normanno, p. 472 This article is highlighted in the In This Issue feature, p. 457

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Cancer Discovery

Tập 1 Số 6

508-523

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