Titre

Frequent 4EBP1 Amplification Induces Synthetic Dependence on FGFR Signaling in Cancer.

Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Mohan, P.
Auteure/Auteur
Pasion, J.
Auteure/Auteur
Ciriello, G.
Auteure/Auteur
Lailler, N.
Auteure/Auteur
de Stanchina, E.
Auteure/Auteur
Viale, A.
Auteure/Auteur
van den Berg, A.
Auteure/Auteur
Diepstra, A.
Auteure/Auteur
Wendel, H.G.
Auteure/Auteur
Sanghvi, V.R.
Auteure/Auteur
Singh, K.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
2072-6694
Statut éditorial
Publié
Date de publication
2022-05-13
Volume
14
Numéro
10
Première page
2397
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory eIF4E-binding protein (4EBP1) is considered a tumor suppressor. The exact molecular effects of 4EBP1 activation in cancer are still unknown. Surprisingly, 4EBP1 is a target of genomic copy number gains (Chr. 8p11) in breast and lung cancer. We noticed that 4EBP1 gains are genetically linked to gains in neighboring genes, including WHSC1L1 and FGFR1. Our results show that FGFR1 gains act to attenuate the function of 4EBP1 via PI3K-mediated phosphorylation at Thr37/46, Ser65, and Thr70 sites. This implies that not 4EBP1 but instead FGFR1 is the genetic target of Chr. 8p11 gains in breast and lung cancer. Accordingly, these tumors show increased sensitivity to FGFR1 and PI3K inhibition, and this is a therapeutic vulnerability through restoring the tumor-suppressive function of 4EBP1. Ribosome profiling reveals genes involved in insulin signaling, glucose metabolism, and the inositol pathway to be the relevant translational targets of 4EBP1. These mRNAs are among the top 200 translation targets and are highly enriched for structure and sequence motifs in their 5'UTR, which depends on the 4EBP1-EIF4E activity. In summary, we identified the translational targets of 4EBP1-EIF4E that facilitate the tumor suppressor function of 4EBP1 in cancer.
Sujets

4EBP1

FGFR1

breast cancer

eIF4E

lung cancer

ribosome footprinting...

PID Serval
serval:BIB_0151C1A5BF17
DOI
PMID
WOS
Permalien
Open Access
Oui
Date de création
2022-06-17T11:55:25.113Z
Date de création dans IRIS
2025-05-20T17:35:45Z
Fichier(s)
En cours de chargement...
Vignette d'image
Nom

35626002_BIB_0151C1A5BF17.pdf

Version du manuscrit

published

Licence

https://creativecommons.org/licenses/by/4.0

Taille

3.97 MB

Format

Adobe PDF

PID Serval

serval:BIB_0151C1A5BF17.P001

URN

urn:nbn:ch:serval-BIB_0151C1A5BF178

Somme de contrôle

(MD5):ed0f250a176fb218a4fb5856c25634b1