Downregulation of c-SRC kinase CSK promotes castration resistant prostate cancer and pinpoints a novel disease subclass

SRC kinase is activated in castration resistant prostate cancer (CRPC), phosphorylates the androgen receptor (AR), and causes its ligand-independent activation as a transcription factor. However, activating SRC mutations are exceedingly rare in human tumors, and mechanisms of ectopic SRC activation...

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Bibliographic Details
Published in:Oncotarget 2015-09, Vol.6 (26), p.22060-22071
Main Authors: Yang, Chih-Cheng, Fazli, Ladan, Loguercio, Salvatore, Zharkikh, Irina, Aza-Blanc, Pedro, Gleave, Martin E, Wolf, Dieter A
Format: Article
Language:English
Subjects:
Animals
Cell Line, Tumor
Cell Proliferation - physiology
Down-Regulation
HEK293 Cells
Heterografts
Humans
Male
Mice
Mice, Inbred NOD
Mice, SCID
Prostatic Neoplasms, Castration-Resistant - enzymology
Prostatic Neoplasms, Castration-Resistant - genetics
Prostatic Neoplasms, Castration-Resistant - pathology
Research Paper
Signal Transduction
src-Family Kinases - genetics
src-Family Kinases - metabolism
Transfection
Xenograft Model Antitumor Assays
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Summary:SRC kinase is activated in castration resistant prostate cancer (CRPC), phosphorylates the androgen receptor (AR), and causes its ligand-independent activation as a transcription factor. However, activating SRC mutations are exceedingly rare in human tumors, and mechanisms of ectopic SRC activation therefore remain largely unknown. Performing a functional genomics screen, we found that downregulation of SRC inhibitory kinase CSK is sufficient to overcome growth arrest induced by depriving human prostate cancer cells of androgen. CSK knockdown led to ectopic SRC activation, increased AR signaling, and resistance to anti-androgens. Consistent with the in vitro observations, stable knockdown of CSK conferred castration resistance in mouse xenograft models, while sensitivity to the tyrosine kinase inhibitor dasatinib was retained. Finally, CSK was found downregulated in a distinct subset of CRPCs marked by AR amplification and ETS2 deletion but lacking PTEN and RB1 mutations. These results identify CSK downregulation as a principal driver of SRC activation and castration resistance and validate SRC as a drug target in a molecularly defined subclass of CRPCs.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.4279