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A System-wide Approach to Monitor Responses to Synergistic BRAF and EGFR Inhibition in Colorectal Cancer Cells

69 Pages Posted: 2 Apr 2018 Publication Status: Review Complete

See all articles by Anna Ressa

Anna Ressa

Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group

Evert Bosdriesz

Netherlands Cancer Institute - Division of Molecular Carcinogenesis

Joep de Ligt

Utrecht University - Cancer Genomics Netherlands

Sara Mainardi

Netherlands Cancer Institute - Division of Molecular Carcinogenesis

Gianluca Maddalo

Royal Institute of Technology (KTH) - Science for Life Laboratory; Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group

Anirudh Prahallad

Netherlands Cancer Institute - Division of Molecular Carcinogenesis; Novartis Institutes for Biomedical Research

Myrthe Jager

Utrecht University - Cancer Genomics Netherlands

Lisanne de la Fonteijne

Utrecht University - Cancer Genomics Netherlands

Martin Fitzpatrick

Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group

Stijn Groten

Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group

A.F. Maarten Altelaar

Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group

René Bernards

Netherlands Cancer Institute - Division of Molecular Carcinogenesis

Edwin Cuppen

Utrecht University - Cancer Genomics Netherlands

Lodewyk Wessels

Netherlands Cancer Institute - Division of Molecular Carcinogenesis; Delft University of Technology - Department of Engineering, Mathematics and Computer Science (EEMCS)

Albert J.R. Heck

Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group

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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 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.

Suggested Citation

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 is a paper under consideration at Cell Press and has not been peer-reviewed.

Anna Ressa

Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group ( email )

Padualaan 8,
Utrecht, 3584 CH
Netherlands

Evert Bosdriesz

Netherlands Cancer Institute - Division of Molecular Carcinogenesis ( email )

Plesmanlaan 121
Amsterdam, 1066 CX
Netherlands

Joep De Ligt

Utrecht University - Cancer Genomics Netherlands

Universiteitsweg 100
Utrecht, 3584 CG
Netherlands

Sara Mainardi

Netherlands Cancer Institute - Division of Molecular Carcinogenesis ( email )

Plesmanlaan 121
Amsterdam, 1066 CX
Netherlands

Gianluca Maddalo

Royal Institute of Technology (KTH) - Science for Life Laboratory

Stockholm, SE-100 44
Sweden

Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group

Padualaan 8,
Utrecht, 3584 CH
Netherlands

Anirudh Prahallad

Netherlands Cancer Institute - Division of Molecular Carcinogenesis

Plesmanlaan 121
Amsterdam, 1066 CX
Netherlands

Novartis Institutes for Biomedical Research

6A-209
250 Massachusetts Avenue
Cambridge, MA 02139
United States

Myrthe Jager

Utrecht University - Cancer Genomics Netherlands

Universiteitsweg 100
Utrecht, 3584 CG
Netherlands

Lisanne De la Fonteijne

Utrecht University - Cancer Genomics Netherlands

Universiteitsweg 100
Utrecht, 3584 CG
Netherlands

Martin Fitzpatrick

Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group

Padualaan 8,
Utrecht, 3584 CH
Netherlands

Stijn Groten

Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group

Padualaan 8,
Utrecht, 3584 CH
Netherlands

A.F. Maarten Altelaar

Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group ( email )

Padualaan 8,
Utrecht, 3584 CH
Netherlands

René Bernards

Netherlands Cancer Institute - Division of Molecular Carcinogenesis

Plesmanlaan 121
Amsterdam, 1066 CX
Netherlands

Edwin Cuppen

Utrecht University - Cancer Genomics Netherlands

Universiteitsweg 100
Utrecht, 3584 CG
Netherlands

Lodewyk Wessels (Contact Author)

Netherlands Cancer Institute - Division of Molecular Carcinogenesis ( email )

Plesmanlaan 121
Amsterdam, 1066 CX
Netherlands

Delft University of Technology - Department of Engineering, Mathematics and Computer Science (EEMCS) ( email )

Mekelweg 4
Delft, 2628 CD
Netherlands

Albert J.R. Heck

Utrecht University - Biomolecular Mass Spectrometry and Proteomics Group ( email )

Padualaan 8,
Utrecht, 3584 CH
Netherlands

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