title: IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies.
abstract: Among patients with colorectal cancer who benefit from therapy targeted to the epidermal growth factor receptor (EGFR), stable disease (SD) occurs more frequently than massive regressions. Exploring the mechanisms of this incomplete sensitivity to devise more efficacious treatments will likely improve patients' outcomes. We tested therapies tailored around hypothesis-generating molecular features in patient-derived xenografts ("xenopatients"), which originated from 125 independent samples that did not harbor established resistance-conferring mutations. Samples from xenopatients that responded to cetuximab, an anti-EGFR agent, with disease stabilization displayed high levels of EGFR family ligands and receptors, indicating high EGFR pathway activity. Five of 21 SD models (23.8%) characterized by particularly high expression of EGFR and EGFR family members regressed after intensified EGFR blockade by cetuximab and a small-molecule inhibitor. In addition, a subset of cases in which enhanced EGFR inhibition was unproductive (6 of 16, 37.5%) exhibited marked overexpression of insulin-like growth factor 2 (IGF2). Enrichment of IGF2 overexpressors among cases with SD was demonstrated in the entire xenopatient collection and was confirmed in patients by mining clinical gene expression data sets. In functional studies, IGF2 overproduction attenuated the efficacy of cetuximab. Conversely, interception of IGF2-dependent signaling in IGF2-overexpressing xenopatients potentiated the effects of cetuximab. The clinical implementation of IGF inhibitors awaits reliable predictors of response, but the results of this study suggest rational combination therapies for colorectal cancer and provide evidence for IGF2 as a biomarker of reduced tumor sensitivity to anti-EGFR therapy and a determinant of response to combined IGF2/EGFR targeting.
authors: Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 10060 Candiolo, Torino, Italy.
authors: Eugenia R
authors: ER
authors: Zanella
authors: Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 10060 Candiolo, Torino, Italy.
authors: Francesco
authors: F
authors: Galimi
authors: Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 10060 Candiolo, Torino, Italy.
authors: Francesco
authors: F
authors: Sassi
authors: Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 10060 Candiolo, Torino, Italy.
authors: Giorgia
authors: G
authors: Migliardi
authors: Translational Cancer Medicine, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 10060 Candiolo, Torino, Italy.
authors: Francesca
authors: F
authors: Cottino
authors: Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 10060 Candiolo, Torino, Italy.
authors: Simonetta M
authors: SM
authors: Leto
authors: Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 10060 Candiolo, Torino, Italy.
authors: Barbara
authors: B
authors: Lupo
authors: Cancer Genetics, Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy.
authors: Jessica
authors: J
authors: Erriquez
authors: Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy. Oncogenomics, Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy.
authors: Claudio
authors: C
authors: Isella
authors: Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy. Molecular Clinical Oncology, Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy.
authors: Paolo M
authors: PM
authors: Comoglio
authors: Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy. Oncogenomics, Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy.
authors: Enzo
authors: E
authors: Medico
authors: University Hospital Gasthuisberg, 3000 Leuven, Belgium.
authors: Sabine
authors: S
authors: Tejpar
authors: Institute of Biostatistics and Analyses, Masaryk University, 611 37 Brno, Czech Republic. Regional Center of Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.
authors: Eva
authors: E
authors: Budinská
authors: Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 10060 Candiolo, Torino, Italy. livio.trusolino@unito.it andrea.bertotti@unito.it.
authors: Livio
authors: L
authors: Trusolino
authors: Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy. Translational Cancer Medicine, Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 10060 Candiolo, Torino, Italy. National Institute of Biostructures and Biosystems, 00136 Rome, Italy. livio.trusolino@unito.it andrea.bertotti@unito.it.
authors: Andrea
authors: A
authors: Bertotti
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D000068818:Cetuximab; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000737:chemistry*; D005091:Exons; D006801:Humans; D007150:Immunohistochemistry; D007335:Insulin-Like Growth Factor II / Q000737:chemistry*; D008024:Ligands; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C035170:IGF2 protein, human; D008024:Ligands; D007335:Insulin-Like Growth Factor II; D066246:ErbB Receptors; D000068818:Cetuximab