The Endosomal Protein CEMIP Links WNT Signaling to MEK1-ERK1/2 Activation in Selumetinib-Resistant Intestinal Organoids.

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.

• Authors: Hong Quan Duong, Ivan Nemazanyy, Florian Rambow, Seng Chuan Tang, Sylvain Delaunay, Lars Tharun, Alexandra Florin, Reinhard Büttner, Daniel Vandaele, Pierre Close, Jean-Christophe Marine, Kateryna Shostak, Alain Chariot
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 16 Pg. 4533-4548 (08 15 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29915160 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• AZD 6244
• Amino Acids
• Benzimidazoles
• MYC protein, human
• Protein Kinase Inhibitors
• Proteins
• Proto-Oncogene Proteins c-fos
• Proto-Oncogene Proteins c-myc
• fos-related antigen 1
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• MAPK1 protein, human
• MAPK3 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• MAP Kinase Kinase 1
• CEMIP protein, human
• Hyaluronoglucosaminidase

Topics

• Amino Acids (genetics)
• Benzimidazoles (pharmacology)
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Drug Resistance, Neoplasm (genetics)
• Endosomes (metabolism, pathology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hyaluronoglucosaminidase
• MAP Kinase Kinase 1 (antagonists & inhibitors, genetics)
• Mitogen-Activated Protein Kinase 1 (genetics)
• Mitogen-Activated Protein Kinase 3 (genetics)
• Organoids (metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Proteins (genetics)
• Proto-Oncogene Proteins B-raf (genetics)
• Proto-Oncogene Proteins c-fos (genetics)
• Proto-Oncogene Proteins c-myc (genetics)
• Wnt Signaling Pathway (genetics)