Titre
RasGRP1 is a potential biomarker to stratify anti-EGFR therapy response in colorectal cancer.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Gbenedio, O.M.
Auteure/Auteur
Bonnans, C.
Auteure/Auteur
Grun, D.
Auteure/Auteur
Wang, C.Y.
Auteure/Auteur
Hatch, A.J.
Auteure/Auteur
Mahoney, M.R.
Auteure/Auteur
Barras, D.
Auteure/Auteur
Matli, M.
Auteure/Auteur
Miao, Y.
Auteure/Auteur
Garcia, K.C.
Auteure/Auteur
Tejpar, S.
Auteure/Auteur
Delorenzi, M.
Auteure/Auteur
Venook, A.P.
Auteure/Auteur
Nixon, A.B.
Auteure/Auteur
Warren, R.S.
Auteure/Auteur
Roose, J.P.
Auteure/Auteur
Depeille, P.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
2379-3708
Statut éditorial
Publié
Date de publication
2019-06-25
Volume
5
Première page
e127552
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Publication Status: epublish
Résumé
Colorectal cancer (CRC) is the third most frequent neoplastic disorder and is a main cause of tumor-related mortality as many patients progress to stage IV metastatic CRC. Standard care consists of combination chemotherapy (FOLFIRI or FOLFOX). Patients with WT KRAS typing are eligible to receive anti-EGFR therapy combined with chemotherapy. Unfortunately, predicting efficacy of CRC anti-EGFR therapy has remained challenging. Here we uncover that the EGFR-pathway component RasGRP1 acts as CRC tumor suppressor in the context of aberrant Wnt signaling. We find that RasGRP1 suppresses EGF-driven proliferation of colonic epithelial organoids. Having established that RasGRP1 dosage levels impacts biology, we focused on CRC patients next. Mining five different data platforms, we establish that RasGRP1 expression levels decrease with CRC progression and predict poor clinical outcome of patients. Lastly, deletion of one or two Rasgrp1 alleles makes CRC spheroids more susceptible to EGFR inhibition. Retrospective analysis of the CALGB80203 clinical trial shows that addition of anti-EGFR therapy to chemotherapy significantly improves outcome for CRC patients when tumors express low RasGRP1 suppressor levels. In sum, RasGRP1 is a unique biomarker positioned in the EGFR pathway and of potential relevance to anti-EGFR therapy for CRC patients.
Sujets
PID Serval
serval:BIB_3AFCE6869632
PMID
Open Access
Oui
Date de création
2019-08-19T09:58:53.597Z
Date de création dans IRIS
2025-05-20T15:37:49Z