title: A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Molecular Pharmacology, Division of Surgical Oncology, Unit of Pathology, Institute for Cancer Research and Treatment, Torino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
authors.forename: Giorgia
authors.initials: G
authors.lastname: Migliardi
authors.forename: Francesco
authors.initials: F
authors.lastname: Galimi
authors.forename: Francesco
authors.initials: F
authors.lastname: Sassi
authors.forename: Davide
authors.initials: D
authors.lastname: Torti
authors.forename: Claudio
authors.initials: C
authors.lastname: Isella
authors.forename: Davide
authors.initials: D
authors.lastname: Corà
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.forename: Michela
authors.initials: M
authors.lastname: Buscarino
authors.forename: Consalvo
authors.initials: C
authors.lastname: Petti
authors.forename: Dario
authors.initials: D
authors.lastname: Ribero
authors.forename: Nadia
authors.initials: N
authors.lastname: Russolillo
authors.forename: Andrea
authors.initials: A
authors.lastname: Muratore
authors.forename: Paolo
authors.initials: P
authors.lastname: Massucco
authors.forename: Alberto
authors.initials: A
authors.lastname: Pisacane
authors.forename: Luca
authors.initials: L
authors.lastname: Molinaro
authors.forename: Emanuele
authors.initials: E
authors.lastname: Valtorta
authors.forename: Andrea
authors.initials: A
authors.lastname: Sartore-Bianchi
authors.forename: Mauro
authors.initials: M
authors.lastname: Risio
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Capussotti
authors.forename: Marcello
authors.initials: M
authors.lastname: Gambacorta
authors.forename: Salvatore
authors.initials: S
authors.lastname: Siena
authors.forename: Enzo
authors.initials: E
authors.lastname: Medico
authors.forename: Anna
authors.initials: A
authors.lastname: Sapino
authors.forename: Silvia
authors.initials: S
authors.lastname: Marsoni
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D000068818:Cetuximab; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D018631:ras Proteins; C508053:ERBB2 protein, human