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 β-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. Cancer Res; 78(16); 4533-48. ©2018 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Duong HQ,Nemazanyy I,Rambow F,Tang SC,Delaunay S,Tharun L,Florin A,Büttner R,Vandaele D,Close P,Marine JC,Shostak K,Chariot Adoi
10.1158/0008-5472.CAN-17-3149subject
Has Abstractpub_date
2018-08-15 00:00:00pages
4533-4548issue
16eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-17-3149journal_volume
78pub_type
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