IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
25632036
DOI
10.1126/scitranslmed.3010445
PII: 7/272/272ra12
Knihovny.cz E-zdroje
- MeSH
- cetuximab MeSH
- chemorezistence MeSH
- erbB receptory chemie MeSH
- exony MeSH
- humanizované monoklonální protilátky terapeutické užití MeSH
- imunohistochemie MeSH
- insulinu podobný růstový faktor II chemie MeSH
- klinické zkoušky jako téma MeSH
- kolorektální nádory farmakoterapie metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- mutace MeSH
- myši MeSH
- nádorové biomarkery metabolismus MeSH
- protinádorové látky terapeutické užití MeSH
- transplantace nádorů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cetuximab MeSH
- erbB receptory MeSH
- humanizované monoklonální protilátky MeSH
- IGF2 protein, human MeSH Prohlížeč
- insulinu podobný růstový faktor II MeSH
- ligandy MeSH
- nádorové biomarkery MeSH
- protinádorové látky 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.
Citace poskytuje Crossref.org
Interrogating open issues in cancer precision medicine with patient-derived xenografts
