Royal Institute of Technology (KTH) - Science for Life Laboratory (SciLife Lab); Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group
Netherlands Cancer Institute - Division of Molecular Carcinogenesis; Delft University of Technology - Department of Engineering, Mathematics and Computer Science (EEMCS); Oncode Institute
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 upregulation of receptors 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 reactivating the MAPK pathway.
Ressa, Anna and Bosdriesz, Evert and de Ligt, Joep and Mainardi, Sara and Maddalo, Gianluca and Prahallad, Anirudh and Jager, Myrthe and de la Fonteijne, Lisanne and Fitzpatrick, Martin and Groten, Stijn and Altelaar, A.F. Maarten and Bernards, René and Cuppen, Edwin and Wessels, Lodewyk and Heck, Albert J.R., A System-wide Approach to Monitor Responses to Synergistic BRAF and EGFR Inhibition in Colorectal Cancer Cells (2018). Available at SSRN: https://ssrn.com/abstract=3151997 or http://dx.doi.org/10.2139/ssrn.3151997
This version of the paper has not been formally peer reviewed.
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