The endosomal protein CEMIP links Wnt signaling to MEK1-ERK1/2 activation in Selumetinib-resistant intestinal organoids

[en] MAPK signaling pathways are constitutively active in colon cancer and also promote acquired resistance to MEK1 inhibition. Here we demonstrate that BRAFV600E-mutated colorectal cancers acquire resistance to MEK1 inhibition by inducing expression of the scaffold protein CEMIP through a beta-catenin- and FRA-1-dependent pathway. CEMIP was found in endosomes and bound MEK1 to sustain ERK1/2 activation in MEK1 inhibitor-resistant BRAFV600E-mutated colorectal cancers. The CEMIP-dependent pathway maintained c-Myc protein levels through ERK1/2 and provided metabolic advantage in resistant cells, potentially by sustaining amino acids synthesis. CEMIP silencing circumvented resistance to MEK1 inhibition, partly, through a decrease of both ERK1/2 signaling and c-Myc. Together, our data identify a cross-talk between Wnt and MAPK signaling cascades, which involves CEMIP. Activation of this pathway promotes survival by potentially regulating levels of specific amino acids via a Myc-associated cascade. Targeting this node may provide a promising avenue for treatment of colon cancers that have acquired resistance to targeted therapies

Research center :

GIGA Molecular Biology of Diseases - ULiège

Disciplines :

Oncology

Author, co-author :

Duong, Hong Quan

Nemazanyy, Ivan

Rambow, Florian

Tang, Seng Chuan ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale

Delaunay, Sylvain ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale

Tharun, Lars

Florin, Alexandra

Büttner, Reinhard

VAN DAELE, Daniel ; Centre Hospitalier Universitaire de Liège - CHU > Service de gastroentérologie, hépatologie, onco. digestive

Close, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale

More authors (3 more)

Language :

English

Title :

The endosomal protein CEMIP links Wnt signaling to MEK1-ERK1/2 activation in Selumetinib-resistant intestinal organoids

Publication date :

18 June 2018

Journal title :

Cancer Research

ISSN :

0008-5472

eISSN :

1538-7445

Publisher :

American Association for Cancer Research, United States

Pages :

DOI: 10.1158/0008-5472.CAN-17-3149

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

WELBIO - Institut wallon virtuel de recherche d'excellence dans les domaines des sciences de la vie [BE]
Fonds Léon Fredericq [BE]
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Fondation contre le Cancer [BE]
Télévie [BE]

Available on ORBi :

since 20 June 2018

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