Format

Send to

Choose Destination
Sci Transl Med. 2015 Jan 28;7(272):272ra12. doi: 10.1126/scitranslmed.3010445.

IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies.

Author information

1
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.
2
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.
3
Cancer Genetics, Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy.
4
Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy. Oncogenomics, Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy.
5
Department of Oncology, University of Torino Medical School, 10060 Candiolo, Torino, Italy. Molecular Clinical Oncology, Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo, Torino, Italy.
6
University Hospital Gasthuisberg, 3000 Leuven, Belgium.
7
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.
8
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.
9
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.

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.

PMID:
25632036
DOI:
10.1126/scitranslmed.3010445
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire Icon for University of Turin Instituional Repository AperTO
Loading ...
Support Center