1. A System-wide Approach to Monitor Responses to Synergistic BRAF and EGFR Inhibition in Colorectal Cancer Cells.
- Author
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Ressa A, Bosdriesz E, de Ligt J, Mainardi S, Maddalo G, Prahallad A, Jager M, de la Fonteijne L, Fitzpatrick M, Groten S, Altelaar AFM, Bernards R, Cuppen E, Wessels L, and Heck AJR
- 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
- 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., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Published
- 2018
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