Metastatic castration-resistant prostate cancer reveals intrapatient similarity and interpatient heterogeneity of therapeutic kinase targets.
Proc Natl Acad Sci U S A
; 110(49): E4762-9, 2013 Dec 03.
Article
en En
| MEDLINE
| ID: mdl-24248375
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fosfoproteínas
/
Proteínas Tirosina Quinasas
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Descubrimiento de Drogas
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Medicina de Precisión
/
Neoplasias de la Próstata Resistentes a la Castración
/
Metástasis de la Neoplasia
Tipo de estudio:
Prognostic_studies
Límite:
Humans
/
Male
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2013
Tipo del documento:
Article