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

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

doi:10.1074/mcp.RA117.000486

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

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

Bioinformatics

Research output: Contribution to Journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1892-1908
Number of pages	17
Journal	Molecular and Cellular Proteomics
Volume	17
Issue number	10
DOIs	https://doi.org/10.1074/mcp.RA117.000486
Publication status	Published - Oct 2018

Bibliographical note

Funding

* This work was conducted under the framework of the Gravity Program CGC.nl, funded by The Netherlands Organisation for Scientific Research (NWO). AR, MA, AJRH were further supported by the Roadmap Initiative Proteins@Work (project number 184.032.201), funded by The Netherlands Organisation for Scientific Research (NWO). □S This article contains supplemental Figures and Tables. The authors declare that they have no conflict of interest. ** To whom correspondence may be addressed: Biomolecular Mass Spectrometry and Proteomics Group, Utrecht Institute for Pharmaceutical Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; E-mail: [email protected]. *** To whom correspondence may be addressed: Division of Molecular Carcinogenesis, Cancer Genomics Centre Netherlands,

Funders	Funder number
Roadmap Initiative Proteins@Work	184.032.201
Nederlandse Organisatie voor Wetenschappelijk Onderzoek

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cell Cycle/drug effects
Cell Line, Tumor
Cell Proliferation/drug effects
Colorectal Neoplasms/genetics
Down-Regulation/drug effects
Drug Synergism
ErbB Receptors/antagonists & inhibitors
Feedback, Physiological
Gene Expression Regulation, Neoplastic/drug effects
Gene Knockout Techniques
Humans
MAP Kinase Signaling System/drug effects
Models, Biological
Mutation/genetics
Phosphatidylinositol 3-Kinases/metabolism
Protein Kinase Inhibitors/pharmacology
Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism
Proto-Oncogene Proteins B-raf/antagonists & inhibitors
Proto-Oncogene Proteins c-akt/metabolism
Systems Biology/methods

Access to Document

10.1074/mcp.RA117.000486

Persistent URL (handle)

Persistent link

Cite this

Ressa, A., Bosdriesz, E., de Ligt, J., Mainardi, S., Maddalo, G., Prahallad, A., Jager, M., de la Fonteijne, L., Fitzpatrick, M., Groten, S., Altelaar, A. F. M., Bernards, R., Cuppen, E., Wessels, L., & Heck, A. J. R. (2018). A System-wide Approach to Monitor Responses to Synergistic BRAF and EGFR Inhibition in Colorectal Cancer Cells. Molecular and Cellular Proteomics, 17(10), 1892-1908. https://doi.org/10.1074/mcp.RA117.000486

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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 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.",

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Ressa, A, Bosdriesz, E, de Ligt, J, Mainardi, S, Maddalo, G, Prahallad, A, Jager, M, de la Fonteijne, L, Fitzpatrick, M, Groten, S, Altelaar, AFM, Bernards, R, Cuppen, E, Wessels, L & Heck, AJR 2018, 'A System-wide Approach to Monitor Responses to Synergistic BRAF and EGFR Inhibition in Colorectal Cancer Cells', Molecular and Cellular Proteomics, vol. 17, no. 10, pp. 1892-1908. https://doi.org/10.1074/mcp.RA117.000486

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AU - Ressa, Anna

AU - Bosdriesz, Evert

AU - de Ligt, Joep

AU - Mainardi, Sara

AU - Maddalo, Gianluca

AU - Prahallad, Anirudh

AU - Jager, Myrthe

AU - de la Fonteijne, Lisanne

AU - Fitzpatrick, Martin

AU - Groten, Stijn

AU - Altelaar, A F Maarten

AU - Bernards, René

AU - Cuppen, Edwin

AU - Wessels, Lodewyk

AU - Heck, Albert J R

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KW - Cell Line, Tumor

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KW - Colorectal Neoplasms/genetics

KW - Down-Regulation/drug effects

KW - Drug Synergism

KW - ErbB Receptors/antagonists & inhibitors

KW - Feedback, Physiological

KW - Gene Expression Regulation, Neoplastic/drug effects

KW - Gene Knockout Techniques

KW - Humans

KW - MAP Kinase Signaling System/drug effects

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KW - Proto-Oncogene Proteins B-raf/antagonists & inhibitors

KW - Proto-Oncogene Proteins c-akt/metabolism

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EP - 1908

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

Persistent URL (handle)

Other files and links

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Cite this