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A System-wide Approach to Monitor Responses to Synergistic BRAF and EGFR Inhibition in Colorectal Cancer Cells
Univ Utrecht, Utrecht Inst Pharmaceut Sci, Biomol Mass Spectrometry & Prote Grp, Padualaan 8, NL-3584 CH Utrecht, Netherlands..
Netherlands Canc Inst, Oncode Inst, Canc Genom Ctr Netherlands, Div Mol Carcinogenesis, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands..ORCID iD: 0000-0002-8788-9548
Univ Utrecht, Univ Med Ctr Utrecht, Div Biomed Genet, Ctr Mol Med & Canc Genom Netherlands, Univ Weg 100, NL-3584 CG Utrecht, Netherlands..ORCID iD: 0000-0002-0348-419X
Netherlands Canc Inst, Oncode Inst, Canc Genom Ctr Netherlands, Div Mol Carcinogenesis, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands..
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2018 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 17, no 10, p. 1892-1908, article id UNSP RA117.000486Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC , 2018. Vol. 17, no 10, p. 1892-1908, article id UNSP RA117.000486
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Clinical Medicine
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URN: urn:nbn:se:kth:diva-269582DOI: 10.1074/mcp.RA117.000486ISI: 000445997400002PubMedID: 29970458Scopus ID: 2-s2.0-85054063415OAI: oai:DiVA.org:kth-269582DiVA, id: diva2:1421760
Note

QC 20200406

Available from: 2020-04-06 Created: 2020-04-06 Last updated: 2020-04-06Bibliographically approved

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Maddalo, Gianluca

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Bosdriesz, Evertde Ligt, JoepMaddalo, GianlucaJager, MyrtheCuppen, EdwinHeck, Albert J. R.
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School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH)Science for Life Laboratory, SciLifeLab
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