| ZANELLA, Eugenia R., Francesco GALIMI, Francesco SASSI, Giorgia MIGLIARDI, Francesca COTTINO, Simonetta M. LETO, Barbara LUPO, Jessica ERRIQUEZ, Claudio ISELLA, Paolo M. COMOGLIO, Enzo MEDICO, Sabine TEJPAR, Eva BUDINSKÁ, Livio TRUSOLINO a Andrea BERTOTTI. IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies. SCIENCE TRANSLATIONAL MEDICINE. WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE, 2015, roč. 7, č. 272, s. "272ra12", 13 s. ISSN 1946-6234. Dostupné z: https://dx.doi.org/10.1126/scitranslmed.3010445. |
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@article{1300089,
author = {Zanella, Eugenia R. and Galimi, Francesco and Sassi, Francesco and Migliardi, Giorgia and Cottino, Francesca and Leto, Simonetta M. and Lupo, Barbara and Erriquez, Jessica and Isella, Claudio and Comoglio, Paolo M. and Medico, Enzo and Tejpar, Sabine and Budinská, Eva and Trusolino, Livio and Bertotti, Andrea},
article_location = {WASHINGTON},
article_number = {272},
doi = {http://dx.doi.org/10.1126/scitranslmed.3010445},
keywords = {epidermal growth factor receptor; colorectal cancer},
language = {eng},
issn = {1946-6234},
journal = {SCIENCE TRANSLATIONAL MEDICINE},
title = {IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies},
volume = {7},
year = {2015}
}
TY - JOUR
ID - 1300089
AU - Zanella, Eugenia R. - Galimi, Francesco - Sassi, Francesco - Migliardi, Giorgia - Cottino, Francesca - Leto, Simonetta M. - Lupo, Barbara - Erriquez, Jessica - Isella, Claudio - Comoglio, Paolo M. - Medico, Enzo - Tejpar, Sabine - Budinská, Eva - Trusolino, Livio - Bertotti, Andrea
PY - 2015
TI - IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies
JF - SCIENCE TRANSLATIONAL MEDICINE
VL - 7
IS - 272
SP - "272ra12"
EP - "272ra12"
PB - AMER ASSOC ADVANCEMENT SCIENCE
SN - 19466234
KW - epidermal growth factor receptor
KW - colorectal cancer
N2 - 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.
ER -
ZANELLA, Eugenia R., Francesco GALIMI, Francesco SASSI, Giorgia MIGLIARDI, Francesca COTTINO, Simonetta M. LETO, Barbara LUPO, Jessica ERRIQUEZ, Claudio ISELLA, Paolo M. COMOGLIO, Enzo MEDICO, Sabine TEJPAR, Eva BUDINSKÁ, Livio TRUSOLINO a Andrea BERTOTTI. IGF2 is an actionable target that identifies a distinct subpopulation of colorectal cancer patients with marginal response to anti-EGFR therapies. \textit{SCIENCE TRANSLATIONAL MEDICINE}. WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE, 2015, roč.~7, č.~272, s.~''272ra12'', 13 s. ISSN~1946-6234. Dostupné z: https://dx.doi.org/10.1126/scitranslmed.3010445.
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