Only a fraction of patients with metastatic colorectal cancer (mCRC) have clinical benefit from therapy with anti-EGFR antibodies, which calls for the identification of novel biomarkers for better personalized medicine. Direct transfer xenografts of tumor surgical specimens conserve the interindividual diversity and the genetic heterogeneity typical of the tumors of origin, potentially combining the flexibility of preclinical analysis with the informative value of population-based studies. We generated cohorts of 85 distinct, genetically characterized mCRC ‘xenopatients’ to discover novel determinants of therapeutic response and new druggable driver oncoproteins. Serially passaged tumors retained the morphological 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 non-responders based on several predictive biomarkers. Genotype-response correlations revealed HER2 amplification/overexpression in 2.7% of unselected tumors and in 36% of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. Importantly, HER2 amplification was also strongly enriched in clinically nonresponsive KRAS wild-type patients. A proof-of-concept, multi-arm study in HER2-amplified xenopatients revealed that the dual EGFR/ERBB2 inhibitor lapatinib led to disease stabilization, whereas pertuzumab, which blocks HER2 heterodimerization, was ineffective. Combinations of lapatinib and pertuzumab or lapatinib and cetuximab induced overt, long-lasting tumor regression. Our suite of patient-derived mCRC xenografts reliably mimicked disease response in humans and prospectively recapitulated biomarker-based case stratification. The impressive efficacy of combined EGFR/HER2 inhibition in HER2-amplified cases suggests promising therapeutic opportunities in cetuximab-resistant mCRC patients, whose medical treatment in the chemorefractory setting remains an unmet clinical need.

A molecularly annotated platform of patient-derived xenografts (‘xenopatients’) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer

BERTOTTI, Andrea;MIGLIARDI, GIORGIA;GALIMI, Francesco;SASSI, FRANCESCO;TORTI, DAVIDE;ISELLA, CLAUDIO;CORA', DAVIDE;DI NICOLANTONIO, Federica;BUSCARINO, MICHELA;PETTI, CONSALVO;MOLINARO, LUCA;MEDICO, Enzo;SAPINO, Anna;COMOGLIO, Paolo;BARDELLI, Alberto;TRUSOLINO, Livio
2011

Abstract

Only a fraction of patients with metastatic colorectal cancer (mCRC) have clinical benefit from therapy with anti-EGFR antibodies, which calls for the identification of novel biomarkers for better personalized medicine. Direct transfer xenografts of tumor surgical specimens conserve the interindividual diversity and the genetic heterogeneity typical of the tumors of origin, potentially combining the flexibility of preclinical analysis with the informative value of population-based studies. We generated cohorts of 85 distinct, genetically characterized mCRC ‘xenopatients’ to discover novel determinants of therapeutic response and new druggable driver oncoproteins. Serially passaged tumors retained the morphological 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 non-responders based on several predictive biomarkers. Genotype-response correlations revealed HER2 amplification/overexpression in 2.7% of unselected tumors and in 36% of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. Importantly, HER2 amplification was also strongly enriched in clinically nonresponsive KRAS wild-type patients. A proof-of-concept, multi-arm study in HER2-amplified xenopatients revealed that the dual EGFR/ERBB2 inhibitor lapatinib led to disease stabilization, whereas pertuzumab, which blocks HER2 heterodimerization, was ineffective. Combinations of lapatinib and pertuzumab or lapatinib and cetuximab induced overt, long-lasting tumor regression. Our suite of patient-derived mCRC xenografts reliably mimicked disease response in humans and prospectively recapitulated biomarker-based case stratification. The impressive efficacy of combined EGFR/HER2 inhibition in HER2-amplified cases suggests promising therapeutic opportunities in cetuximab-resistant mCRC patients, whose medical treatment in the chemorefractory setting remains an unmet clinical need.
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http://cancerdiscovery.aacrjournals.org/content/1/6/508.long
GROWTH-FACTOR RECEPTOR; IN-SITU HYBRIDIZATION; GENE COPY NUMBER; PHASE-III TRIAL; 1ST-LINE TREATMENT; MICROSATELLITE INSTABILITY; PROGNOSTIC-FACTOR; PLUS IRINOTECAN; MUTATION STATUS; PANITUMUMAB
Bertotti A; Migliardi G; Galimi F; Sassi F; Torti D; Isella C; Corà D; Di Nicolantonio F; Buscarino M; Petti C; Ribero D; Russolillo N; Muratore A; Massucco P; Pisacane A; Molinaro L; Valtorta E; Sartore-Bianchi A; Risio M; Capussotti L; Gambacorta M; Siena S; Medico E; Sapino A; Marsoni S; Comoglio PM; Bardelli A†; Trusolino L† (†Co-Senior authors)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/96346
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