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  Phosphosignature Predicts Dasatinib Response in Non-small Cell Lung Cancer

Klammer, M., Kaminski, M., Zedler, A., Oppermann, F., Blencke, S., Marx, S., et al. (2012). Phosphosignature Predicts Dasatinib Response in Non-small Cell Lung Cancer. MOLECULAR & CELLULAR PROTEOMICS, 11(9), 651-668. doi:10.1074/mcp.M111.016410.

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 Creators:
Klammer, Martin1, Author
Kaminski, Marc1, Author
Zedler, Alexandra1, Author
Oppermann, Felix1, Author
Blencke, Stephanie1, Author
Marx, Sandra1, Author
Mueller, Stefan1, Author
Tebbe, Andreas1, Author              
Godl, Klaus1, Author
Schaab, Christoph2, 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: NUCLEOTIDE EXCHANGE FACTOR; METASTATIC BREAST-CANCER; QUANTITATIVE PROTEOMICS; INTEGRIN ALPHA-6-BETA-4; PROTEIN-PHOSPHORYLATION; MONOCLONAL-ANTIBODY; SIGNALING PATHWAYS; MASS-SPECTROMETRY; KINASE INHIBITOR; PHASE-II
 Abstract: Targeted drugs are less toxic than traditional chemotherapeutic therapies; however, the proportion of patients that benefit from these drugs is often smaller. A marker that confidently predicts patient response to a specific therapy would allow an individual therapy selection most likely to benefit the patient. Here, we used quantitative mass spectrometry to globally profile the basal phosphoproteome of a panel of non-small cell lung cancer cell lines. The effect of the kinase inhibitor dasatinib on cellular growth was tested against the same panel. From the phosphoproteome profiles, we identified 58 phosphorylation sites, which consistently differ between sensitive and resistant cell lines. Many of the corresponding proteins are involved in cell adhesion and cytoskeleton organization. We showed that a signature of only 12 phosphorylation sites is sufficient to accurately predict dasatinib sensitivity. Four of the phosphorylation sites belong to integrin beta 4, a protein that mediates cell-matrix or cell-cell adhesion. The signature was validated in cross-validation and label switch experiments and in six independently profiled breast cancer cell lines. The study supports that the phosphorylation of integrin beta 4, as well as eight further proteins comprising the signature, are candidate biomarkers for predicting response to dasatinib in solid tumors. Furthermore, our results show that identifying predictive phosphorylation signatures from global, quantitative phosphoproteomic data is possible and can open a new path to discovering molecular markers for response prediction. Molecular & Cellular Proteomics 11: 10.1074/mcp.M111.016410, 651-668, 2012.

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Language(s): eng - English
 Dates: 2012-09
 Publication Status: Published in print
 Pages: 18
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000310209300010
DOI: 10.1074/mcp.M111.016410
 Degree: -

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Title: MOLECULAR & CELLULAR PROTEOMICS
Source Genre: Journal
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Publ. Info: 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Pages: - Volume / Issue: 11 (9) Sequence Number: - Start / End Page: 651 - 668 Identifier: ISSN: 1535-9476