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A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells

By Anna Ressa, Evert Bosdriesz, Joep de Ligt, Sara Mainardi, Gianluca Maddalo, Anirudh Prahallad, Myrthe Jager, Lisanne de la Fonteijne, Martin Fitzpatrick, Stijn Groten, Maarten Altelaar, René Bernards, Edwin Cuppen, Lodewyk Wessels, Albert J.R. Heck

Posted 27 Sep 2017
bioRxiv DOI: 10.1101/194845 (published DOI: 10.1074/mcp.ra117.000486)

Intrinsic and/or acquired resistance represents one of the challenges in 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 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.

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