期刊
CANCER RESEARCH
卷 78, 期 16, 页码 4533-4548出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-3149
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资金
- Belgian National Funds for Scientific Research (FNRS)
- Concerted Research Action Program (Bio-Acet) at the University of Liege
- Special Research Funds (FSR) at the University of Liege
- Belgian Foundation against Cancer [FAF-F/2016/794]
- Walloon Excellence in Life Sciences and Biotechnology [WELBIO-CR-2015A-02]
- Max Planck Society
- Fonds Leon Fredericq
- Centre Anticancereux of the CHU Liege
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.
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