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  Phosphoproteome Profiling Reveals Molecular Mechanisms of Growth-Factor-Mediated Kinase Inhibitor Resistance in EGFR-Overexpressing Cancer Cells

Koch, H., Wilhelm, M., Ruprecht, B., Beck, S., Frejno, M., Klaeger, S., et al. (2016). Phosphoproteome Profiling Reveals Molecular Mechanisms of Growth-Factor-Mediated Kinase Inhibitor Resistance in EGFR-Overexpressing Cancer Cells. Journal of Proteome Research, 15(12), 4490-4504. doi:10.1021/acs.jproteome.6b00621.

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 Creators:
Koch, Heiner1, Author
Wilhelm, Mathias1, Author
Ruprecht, Benjamin1, Author
Beck, Scarlet2, Author              
Frejno, Martin1, Author
Klaeger, Susan1, Author
Kuster, Bernhard1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: RECEPTOR-TYROSINE KINASE; LIGHT-CHAIN KINASE; LUNG-CANCER; BREAST-CANCER; IN-VIVO; ACQUIRED-RESISTANCE; PANCREATIC-CANCER; GEFITINIB; PROTEIN; FAMILYBiochemistry & Molecular Biology; Drug resistance; tumor microenvironment; EGFR; kinase inhibitors; mass spectrometry; quantitative proteomics; phosphoproteomics;
 Abstract: Although substantial progress has been made regarding the use of molecularly targeted cancer therapies, resistance almost invariably develops and presents a major clinical challenge. The tumor microenvironment can rescue cancer cells from kinase inhibitors by growth-factor mediated induction of pro-survival pathways. Here we show that epidermal growth factor receptor (EGFR) inhibition by Gefitinib is counteracted by growth factors, notably FGF2, and we assessed the global molecular consequences of this resistance at the proteome and phosphoproteome level in A431 cells. Tandem mass tag peptide labeling and quantitative mass spectrometry allowed the identification and quantification of 22 000 phosphopeptides and 8800 proteins in biological triplicates without missing values. The data show that FGF2 protects the cells from the antiproliferative effect of Gefitinib and largely prevents reprogramming of the proteome and phosphoproteome. Simultaneous EGFR/FGFR or EGFR/GSG2 (Haspin) inhibition overcomes this resistance, and the phosphoproteomic experiments further prioritized the RAS/MEK/ERK as well as the PI3K/mTOR axis for combination treatment. Consequently, the MEK inhibitor Trametinib prevented FGF2-mediated survival of EGFR inhibitor-resistant cells when used in combination with Gefitinib. Surprisingly, the PI3K/mTOR inhibitor Omipalisib reversed resistance mediated by all four growth factors tested, making it an interesting candidate for mitigating the effects of the tumor microenvironment.

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Language(s): eng - English
 Dates: 2016-10-302016
 Publication Status: Published in print
 Pages: 15
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: Journal of Proteome Research
  Other : J. Proteome Res.
Source Genre: Journal
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Publ. Info: Washington, D.C. : American Chemical Society
Pages: - Volume / Issue: 15 (12) Sequence Number: - Start / End Page: 4490 - 4504 Identifier: ISSN: 1535-3893
CoNE: https://pure.mpg.de/cone/journals/resource/111019664290000