Universität zu Köln

Nemazanyy, Ivan, Rambow, Florian, Tang, Seng Chuan, Delaunay, Sylvain, Tharun, Lars, Florin, Alexandra, Buttner, Reinhard, Vandaele, Daniel, Close, Pierre, Marine, Jean-Christophe ORCID: 0000-0003-2433-9837, Shostak, Kateryna and Chariot, Alain (2018). The Endosomal Protein CEMIP Links WNT Signaling to MEK1-ERK1/2 Activation in Selumetinib-Resistant Intestinal Organoids. Cancer Res., 78 (16). S. 4533 - 4549. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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Abstract

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. Significance: MEK1 inhibitor-resistant colorectal cancer relies on the scaffold and endosomal protein CEMIP to maintain ERK1/2 signaling and Myc-driven transcription. (C) 2018 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Nemazanyy, Ivan UNSPECIFIED UNSPECIFIED UNSPECIFIED Rambow, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Tang, Seng Chuan UNSPECIFIED UNSPECIFIED UNSPECIFIED Delaunay, Sylvain UNSPECIFIED UNSPECIFIED UNSPECIFIED Tharun, Lars UNSPECIFIED UNSPECIFIED UNSPECIFIED Florin, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Buttner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Vandaele, Daniel UNSPECIFIED UNSPECIFIED UNSPECIFIED Close, Pierre UNSPECIFIED UNSPECIFIED UNSPECIFIED Marine, Jean-Christophe UNSPECIFIED orcid.org/0000-0003-2433-9837 UNSPECIFIED Shostak, Kateryna UNSPECIFIED UNSPECIFIED UNSPECIFIED Chariot, Alain UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-176421
DOI:	10.1158/0008-5472.CAN-17-3149
Journal or Publication Title:	Cancer Res.
Volume:	78
Number:	16
Page Range:	S. 4533 - 4549
Date:	2018
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language COLORECTAL-CANCER; COLON-CANCER; POOR-PROGNOSIS; ACQUIRED-RESISTANCE; MEK INHIBITION; C-MYC; BRAF; EGFR; METABOLISM; SURVIVAL Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/17642