Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression

Justin M. Drake, Nicholas A. Graham, Tanya Stoyanova, Amir Sedghi, Andrew S. Goldstein, Houjian Cai, Daniel A. Smith, Hong Zhangh, Evangelia Komisopoulou, Jiaoti Huang, Thomas G. Graeber, Owen N. Witte

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94 Scopus citations

Abstract

Dominant mutations or DNA amplification of tyrosine kinases are rare among the oncogenic alterations implicated in prostate cancer. We demonstrate that castration-resistant prostate cancer (CRPC) in men exhibits increased tyrosine phosphorylation, raising the question of whether enhanced tyrosine kinase activity is observed in prostate cancer in the absence of specific tyrosine kinase mutation or DNA amplification. We generated a mouse model of prostate cancer progression using commonly perturbed non-tyrosine kinase oncogenes and pathways and detected a significant up-regulation of tyrosine phosphorylation at the carcinoma stage. Phosphotyrosine peptide enrichment and quantitative mass spectrometry identified oncogene-specific tyrosine kinase signatures, including activation of EGFR, ephrin type-A receptor 2 (EPHA2), and JAK2. Kinase:substrate relationship analysis of the phosphopeptides also revealed ABL1 and SRC tyrosine kinase activation. The observation of elevated tyrosine kinase signaling in advanced prostate cancer and identification of specific tyrosine kinase pathways from genetically defined tumor models point to unique therapeutic approaches using tyrosine kinase inhibitors for advanced prostate cancer.

Original languageEnglish (US)
Pages (from-to)1643-1648
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number5
DOIs
StatePublished - Jan 31 2012

Keywords

  • AKT
  • Androgen receptor
  • Bioinformatics
  • ERG
  • K-RAS

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    Drake, J. M., Graham, N. A., Stoyanova, T., Sedghi, A., Goldstein, A. S., Cai, H., Smith, D. A., Zhangh, H., Komisopoulou, E., Huang, J., Graeber, T. G., & Witte, O. N. (2012). Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression. Proceedings of the National Academy of Sciences of the United States of America, 109(5), 1643-1648. https://doi.org/10.1073/pnas.1120985109