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A Molecularly Annotated Platform of Patient-Derived Xenografts (“Xenopatients”) Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer
Open accessPublished version of a preprint
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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“HER2 overexpression is a negative predictor associated with reduced efficacy of anti-EGFR therapy [31], and >36% of cetuximab-resistant mCRC with wild-type KRAS, NRAS, BRAF, and PI3K was found to display HER2 overexpression [32].”
From Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment (2024) · cites this paper as [32]
In the citing paper
“A series of studies have demonstrated that HER2 gene amplification or activating mutations can mediate resistance to anti-EGFR mAbs in CRC [27,178,179].”
From Drug Resistance in Colorectal Cancer: From Mechanism to Clinic (2022) · cites this paper as [27]
In the citing paper
“Preclinical studies have shown that the combination of HER2 and EGFR blockade can lead to CRC tumor regression [27,28,29].”
From Drug Resistance in Colorectal Cancer: From Mechanism to Clinic (2022) · cites this paper as [27]
In the citing paper
“Two independent studies have recently shown that HER2 amplification is a predictor of poor sensitivity to anti-EGFR antibodies [91, 92].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [91]
In the citing paper
“In retrospective studies, patients with tumors featuring HER2 amplification or heregulin overexpression and treated with cetuximab or panitumumab experienced disease progression and shorter progression-free and overall survival compared with HER2 wild-type cases [91-93].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [91]
In the citing paper
“only the dual targeting of HER2 and EGFR by combining a small-molecule inhibitor, such as the dual EGFR/HER2 inhibitor lapatinib, with a moAb, such as cetuximab or pertuzumab, induced overt and long-lasting tumor regressions in proof-of-concept trials in HER2-amplified xenopatients [91].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [91]
In the citing paper
“Increased EGFR gene copy number could predict response among KRAS wild-type patients [53, 91, 111-113]”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [91]
In the citing paper
“Strong preclinical evidence suggests that dual inhibition of ERBB2 is superior to monotherapy due to enhanced efficacy and reduced therapy resistance4648”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [46]
In the citing paper
“Bertotti et al. identified ERBB2 as a biomarker of resistance to anti-EGFR mAbs [113].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [113]
In the citing paper
“A total of 2–7% of unselected CRCs were found to have ERBB2/mutations, and this number was much higher in KRAS wild-type cases (13.6%) and in KRAS/NRAS/BRAF/PIK3CA quadruple wild-type cases (36% )[13, 113, 114].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [113]
In the citing paper
“Finally, using patient-derived colon cancer xenografts, Bertotti et al. identified HER2 gene amplification as a predictor of resistance to cetuximab among KRAS wild-type tumors (Bertotti et al., 2011).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Bertotti et al., 2011
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Metadata
- Authors
- 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, P. M., Bardelli, A., & Trusolino, L.
- Affiliations
- IFOM (IT)
- Authors' 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
- ORCID
- Venue
- Cancer Discovery
- Published
- 2011-11-01
- Volume
- 1
- Issue
- 6
- Pages
- 508-523
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W1987443121
- Cited by
- 939
- References
- 56
- Citations by year
- 2026: 24 · 2025: 42 · 2024: 46 · 2023: 79 · 2022: 72 · 2021: 74 · 2020: 71 · 2019: 86 · 2018: 86 · 2017: 90 · 2016: 71 · 2015: 62 · 2014: 60 · 2013: 48 · 2012: 23
- FWCI
- 21.44
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- other-oa
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro
- Regione Piemonte
- Genentech
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- patient-derived xenografts, metastatic colorectal cancer, cetuximab resistance, HER2 amplification, anti-EGFR therapy, predictive biomarkers, combination therapy, KRAS wild-type, BRAF wild-type, treatment resistance, tumor heterogeneity
- MeSH terms
- Cetuximab, Aged, Aged, 80 and over, Animals, Antibodies, Monoclonal, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Prospective Studies, Biomarkers, Tumor, Colorectal Neoplasms, ras Proteins, Receptor, ErbB-2, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Mice, Molecular Targeted Therapy, Antibodies, Monoclonal, Humanized, ErbB Receptors
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