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

被引：762

作者：

Bertotti, Andrea ^{[1
,8
]}

Migliardi, Giorgia ^{[1
,8
]}

Galimi, Francesco ^{[1
]}

Sassi, Francesco ^{[1
,8
]}

Torti, Davide ^{[1
,8
]}

Isella, Claudio ^{[2
]}

Cora, Davide ^{[3
]}

Di Nicolantonio, Federica ^{[11
]}

Buscarino, Michela ^{[4
]}

Petti, Consalvo ^{[2
]}

Ribero, Dario ^{[10
]}

Russolillo, Nadia ^{[10
]}

Muratore, Andrea ^{[5
]}

Massucco, Paolo ^{[5
]}

Pisacane, Alberto ^{[6
]}

Molinaro, Luca ^{[9
]}

Valtorta, Emanuele ^{[12
]}

Sartore-Bianchi, Andrea ^{[13
]}

Risio, Mauro ^{[6
]}

Capussotti, Lorenzo ^{[10
]}

Gambacorta, Marcello ^{[12
]}

Siena, Salvatore ^{[13
]}

Medico, Enzo ^{[2
,8
]}

Sapino, Anna ^{[9
]}

Marsoni, Silvia ^{[7
,14
]}

Comoglio, Paolo M. ^{[8
]}

Bardelli, Alberto ^{[4
,11
]}

Trusolino, Livio ^{[1
,8
]}

机构：

[1] Inst Canc Res & Treatment, Mol Pharmacol Lab, I-10060 Turin, Italy

[2] Inst Canc Res & Treatment, Lab Oncogen, I-10060 Turin, Italy

[3] Inst Canc Res & Treatment, Lab Syst Biol, I-10060 Turin, Italy

[4] Inst Canc Res & Treatment, Mol Genet Lab, I-10060 Turin, Italy

[5] Inst Canc Res & Treatment, Div Surg Oncol, I-10060 Turin, Italy

[6] Inst Canc Res & Treatment, Unit Pathol, I-10060 Turin, Italy

[7] Inst Canc Res & Treatment, Clin Coordinat Unit, I-10060 Turin, Italy

[8] Univ Turin, Sch Med, Dept Oncol Sci, Turin, Italy

[9] Univ Turin, Sch Med, Dept Biomed Sci & Human Oncol, Turin, Italy

[10] Mauriziano Umberto Hosp, Dept Surg, Turin, Italy

[11] FIRC Inst Mol Oncol, Milan, Italy

[12] Osped Niguarda Ca Granda, Div Pathol, Milan, Italy

[13] Osped Niguarda Ca Granda, Falck Div Med Oncol, Milan, Italy

[14] So Europe New Drug Org Fdn, Milan, Italy

来源：

CANCER DISCOVERY | 2011年 / 1卷 / 06期

关键词：

GROWTH-FACTOR RECEPTOR; IN-SITU HYBRIDIZATION; GENE COPY NUMBER; PHASE-III TRIAL; 1ST-LINE TREATMENT; MICROSATELLITE INSTABILITY; PROGNOSTIC-FACTOR; PLUS IRINOTECAN; MUTATION STATUS; PANITUMUMAB;

D O I：

10.1158/2159-8290.CD-11-0109

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C) 2011 AACR.

引用

页码：508 / 523

页数：16

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