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A System-wide Approach to Monitor Responses to Synergistic BRAF and EGFR Inhibition in Colorectal Cancer Cells.
- Source :
-
Molecular & cellular proteomics : MCP [Mol Cell Proteomics] 2018 Oct; Vol. 17 (10), pp. 1892-1908. Date of Electronic Publication: 2018 Jul 03. - Publication Year :
- 2018
-
Abstract
- Intrinsic and/or acquired resistance represents one of the great challenges in targeted cancer therapy. A deeper understanding of the molecular biology of cancer has resulted in more efficient strategies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has also been observed in colorectal cancer patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block intrinsic resistance to BRAF inhibitors. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant colorectal cancer cells as a model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both known and novel responses. We primarily observe widespread up-regulation of receptor tyrosine kinases and metabolic pathways upon BRAF inhibition. These findings point to mechanisms by which the drug-treated cells switch energy sources and enter a quiescent-like state as a defensive response, while additionally compensating for the MAPK pathway inhibition.<br /> (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Cell Cycle drug effects
Cell Line, Tumor
Cell Proliferation drug effects
Colorectal Neoplasms genetics
Down-Regulation drug effects
Drug Synergism
ErbB Receptors metabolism
Feedback, Physiological
Gene Expression Regulation, Neoplastic drug effects
Gene Knockout Techniques
Humans
MAP Kinase Signaling System drug effects
Models, Biological
Mutation genetics
Phosphatidylinositol 3-Kinases metabolism
Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism
Proto-Oncogene Proteins B-raf metabolism
Proto-Oncogene Proteins c-akt metabolism
Colorectal Neoplasms pathology
ErbB Receptors antagonists & inhibitors
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins B-raf antagonists & inhibitors
Systems Biology methods
Subjects
Details
- Language :
- English
- ISSN :
- 1535-9484
- Volume :
- 17
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Molecular & cellular proteomics : MCP
- Publication Type :
- Academic Journal
- Accession number :
- 29970458
- Full Text :
- https://doi.org/10.1074/mcp.RA117.000486