Ítem


Interferon/STAT1 and neuregulin signaling pathways are exploratory biomarkers of cetuximab (Erbitux®) efficacy in KRAS wild-type squamous carcinomas: A pathway-based analysis of whole human-genome microarray data from cetuximab-adapted tumor cell-line models

KRAS mutation status is being used as the sole biomarker to predict therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A significant number of mCRC patients with KRAS wild-type (WT) tumors, however, do not benefit from cetuximab. We are also lacking efficacy predictors in head and neck squamous cell carcinomas with an intact KRAS signaling and in non-small cell lung cancer in which KRAS mutations do not predict cetuximab efficacy. We recently established pre-clinical models of EGFR gene-amplified KRAS WT A431 squamous carcinoma cells chronically adapted to grow in the presence of cetuximab. We employed the ingenuity pathway analysis software to functionally interpret data from Agilent’s whole human genome arrays in the context of biological processes, networks, and pathways. Cetuximab-induced activation of the interferon (IFN)/STAT1 appeared to switch from ‘growth inhibitory’ in acutely-treated cells to ‘pro-survival’ in chronically-adapted cells. Cetuximab treatment appeared to negatively select initially dominant IFN-sensitive clones and promoted selection of IFN- and cetuximab-refractory tumor clones constitutively bearing an up-regulated IFN/STAT1 signaling. High-levels of mRNAs coding for the EGFR ligands amphiregulin (AREG), epiregulin (EREG), and neuregulin-1/heregulin (NRG1) predicted for acute cetuximab’s functioning. Chronic cetuximab, however, appeared to negatively select initially dominant AREG/EREG/NRG1-positive clones to promote selection of cetuximab-refractory clones exhibiting a knocked-down neuregulin signaling. Our current evolutionary mapping of the transcriptomic changes that occur during cetuximab-induced chronic blockade of EGFR/KRAS WT signaling strongly suggests that mRNAs coding for IFN/STAT1- and EGFR ligands-related genes can be evaluated as novel predictors of efficacy in KRAS WT squamous cancer patients being treated with cetuximab

© International Journal of Oncology, 2011, vol. 39, núm. 6, p. 1455-1479

Spandidos Publications

Autor: Oliveras Ferrarós, Cristina
Vázquez Martín, Alejandro
Queralt, Bernardo
Adrados, Manuel
Ortiz, Rosa
Cufí González, Sílvia
Hernández Yagüe, Xavier
Guardeño, Raquel
Báez, Luciana
Martin Castillo, Begoña
Pérez Martínez, Maria Carmen
López Bonet, Eugeni
Llorens Duran, Rafael de
Bernadó, Luis
Brunet i Vidal, Joan
Menéndez Menéndez, Javier Abel
Data: 2011
Resum: KRAS mutation status is being used as the sole biomarker to predict therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A significant number of mCRC patients with KRAS wild-type (WT) tumors, however, do not benefit from cetuximab. We are also lacking efficacy predictors in head and neck squamous cell carcinomas with an intact KRAS signaling and in non-small cell lung cancer in which KRAS mutations do not predict cetuximab efficacy. We recently established pre-clinical models of EGFR gene-amplified KRAS WT A431 squamous carcinoma cells chronically adapted to grow in the presence of cetuximab. We employed the ingenuity pathway analysis software to functionally interpret data from Agilent’s whole human genome arrays in the context of biological processes, networks, and pathways. Cetuximab-induced activation of the interferon (IFN)/STAT1 appeared to switch from ‘growth inhibitory’ in acutely-treated cells to ‘pro-survival’ in chronically-adapted cells. Cetuximab treatment appeared to negatively select initially dominant IFN-sensitive clones and promoted selection of IFN- and cetuximab-refractory tumor clones constitutively bearing an up-regulated IFN/STAT1 signaling. High-levels of mRNAs coding for the EGFR ligands amphiregulin (AREG), epiregulin (EREG), and neuregulin-1/heregulin (NRG1) predicted for acute cetuximab’s functioning. Chronic cetuximab, however, appeared to negatively select initially dominant AREG/EREG/NRG1-positive clones to promote selection of cetuximab-refractory clones exhibiting a knocked-down neuregulin signaling. Our current evolutionary mapping of the transcriptomic changes that occur during cetuximab-induced chronic blockade of EGFR/KRAS WT signaling strongly suggests that mRNAs coding for IFN/STAT1- and EGFR ligands-related genes can be evaluated as novel predictors of efficacy in KRAS WT squamous cancer patients being treated with cetuximab
Format: application/pdf
ISSN: 1019-6439 (versió paper)
1791-2423 (versió electrònica)
Accés al document: http://hdl.handle.net/10256/8262
Llenguatge: eng
Editor: Spandidos Publications
Col·lecció: Reproducció digital del document publicat a: http://www.spandidos-publications.com/ijo/39/6/1455
Articles publicats (D-B)
És part de: © International Journal of Oncology, 2011, vol. 39, núm. 6, p. 1455-1479
Drets: Tots els drets reservats
Matèria: Recte -- Càncer
Rectum -- Cancer
Marcadors tumorals
Tumor markers
Títol: Interferon/STAT1 and neuregulin signaling pathways are exploratory biomarkers of cetuximab (Erbitux®) efficacy in KRAS wild-type squamous carcinomas: A pathway-based analysis of whole human-genome microarray data from cetuximab-adapted tumor cell-line models
Tipus: info:eu-repo/semantics/article
Repositori: DUGiDocs

Matèries

Autors