IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25632036
DOI
10.1126/scitranslmed.3010445
PII: 7/272/272ra12
Knihovny.cz E-resources
- MeSH
- Cetuximab MeSH
- Drug Resistance, Neoplasm MeSH
- ErbB Receptors chemistry MeSH
- Exons MeSH
- Antibodies, Monoclonal, Humanized therapeutic use MeSH
- Immunohistochemistry MeSH
- Insulin-Like Growth Factor II chemistry MeSH
- Clinical Trials as Topic MeSH
- Colorectal Neoplasms drug therapy metabolism MeSH
- Humans MeSH
- Ligands MeSH
- Mutation MeSH
- Mice MeSH
- Biomarkers, Tumor metabolism MeSH
- Antineoplastic Agents therapeutic use MeSH
- Neoplasm Transplantation MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Cetuximab MeSH
- ErbB Receptors MeSH
- Antibodies, Monoclonal, Humanized MeSH
- IGF2 protein, human MeSH Browser
- Insulin-Like Growth Factor II MeSH
- Ligands MeSH
- Biomarkers, Tumor MeSH
- Antineoplastic Agents MeSH
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.
References provided by Crossref.org
Interrogating open issues in cancer precision medicine with patient-derived xenografts
