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

None, None; None, None; None, None; None, None; None, None; None, None; None, None; None, None; None, None; None, None; None, None; None, None; None, None; None, None; None, None

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

Journal Article (2018)

Author(s)

Anna Ressa (Universiteit Utrecht)

Evert Bosdriesz (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Joep De Ligt ( University Medical Centre Utrecht)

Sara Mainardi (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Gianluca Maddalo (Universiteit Utrecht)

Anirudh Prahallad (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Myrthe Jager ( University Medical Centre Utrecht)

Lisanne De La Fonteijne ( University Medical Centre Utrecht)

Martin Fitzpatrick (Universiteit Utrecht)

Stijn Groten (Universiteit Utrecht)

A.F. Maarten Altelaar (Universiteit Utrecht)

René Bernards (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Edwin Cuppen ( University Medical Centre Utrecht)

Lodewyk Wessels (TU Delft - Pattern Recognition and Bioinformatics, Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)

Albert J.R. Heck (Universiteit Utrecht)

DOI related publication

https://doi.org/10.1074/mcp.RA117.000486 Final published version

To reference this document use

https://resolver.tudelft.nl/uuid:ded35f02-e896-46ed-a41e-4cf7c8d330b1

More Info

expand_more

Publication Year

2018

Language

English

Journal title

Molecular and Cellular Proteomics

Issue number

10

Volume number

17

Pages (from-to)

1892-1908

Downloads counter

294

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.