Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 49, Pages E4762-E4769Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1319948110
Keywords
metastasis; resistance; personalized medicine; combination therapy; phosphotyrosine
Categories
Funding
- Department of Defense Prostate Cancer Research Program [W81XWH-11-1-0504, W81XWH-12-1-0100, W81XWH-11-1-0227, W81XWH-12-1-0206]
- UCLA Scholars in Oncologic Molecular Imaging (SOMI) program, National Institutes of Health (NIH) [R25T CA098010]
- NIH [5T32CA009297-28, U54 CA163124, NIH 1 U01CA143055-01A1, NIH 2 P50 CA69568, NIH 1 PO1 CA093900]
- UCLA Specialty Training and Advanced Research (STAR) Program
- UCLA Medical Scientist Training Program
- UCLA Specialized Program in Research Excellence (SPORE) in prostate cancer, National Cancer Institute (NCI) [1R01CA158627]
- Stand Up to Cancer/AACR Dream Team Award
- Prostate Cancer Foundation Honorable A. David Mazzone Special Challenge Award
- Prostate Cancer Foundation
- Taubman Research Institute as a Taubman Scholar
- American Cancer Society
- NCI/NIH [P01 CA168585, R21 CA169993]
- American Cancer Society Research Scholar Award [RSG-12-257-01-TBE]
- CalTech-UCLA Joint Center for Translational Medicine
- UCLA Jonsson Cancer Center Foundation
- UCLA Institute for Molecular Medicine
- National Center for Advancing Translational Sciences UCLA Clinical and Translational Science Institute (CTSI) [UL1TR000124]
- Concern Fondation CONquer CanCER Now Award
- Stand Up to Cancer/American Association for Cancer Research (AACR)/Prostate Cancer Foundation
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In prostate cancer, multiple metastases from the same patient share similar copy number, mutational status, erythroblast transformation specific (ETS) rearrangements, and methylation patterns supporting their clonal origins. Whether actionable targets such as tyrosine kinases are also similarly expressed and activated in anatomically distinct metastatic lesions of the same patient is not known. We evaluated active kinases using phosphotyrosine peptide enrichment and quantitative mass spectrometry to identify druggable targets in metastatic castration-resistant prostate cancer obtained at rapid autopsy. We identified distinct phosphopeptide patterns in metastatic tissues compared with treatment-naive primary prostate tissue and prostate cancer cell line-derived xenografts. Evaluation of metastatic castration-resistant prostate cancer samples for tyrosine phosphorylation and upstream kinase targets revealed SRC, epidermal growth factor receptor (EGFR), rearranged during transfection (RET), anaplastic lymphoma kinase (ALK), and MAPK1/3 and other activities while exhibiting intrapatient similarity and interpatient heterogeneity. Phosphoproteomic analyses and identification of kinase activation states in metastatic castration-resistant prostate cancer patients have allowed for the prioritization of kinases for further clinical evaluation.
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