期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 109, 期 5, 页码 1643-1648出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1120985109
关键词
AKT; androgen receptor; ERG; K-RAS; bioinformatics
资金
- Department of Defense [PC101928, PC101008]
- UCLA
- US Department of Health and Human Services
- Ruth L. Kirschstein Institutional National Research Service [T32 CA009056]
- California Institute [TG2-01169]
- Specialized Program of Research Excellence (SPORE) in Prostate Cancer
- UCLA SPORE in Prostate Cancer
- CalTech UCLA Joint Center
- National Cancer Institute [1R01CA158627-01]
- Prostate Cancer Foundation
- Investigator of the Howard Hughes Medical Institute
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.
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