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Oncotarget. 2015 Sep 8;6(26):22060-71.

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

Author information

1
Tumor Initiation & Maintenance Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
2
Functional Genomics Core, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
3
Vancouver Prostate Centre, Vancouver, BC, Canada V6H 3Z6.
4
San Diego Center for Systems Biology, La Jolla, CA 92037, USA.
5
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
6
Tumor Analysis Core, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
7
School of Pharmaceutical Sciences & Center for Stress Signaling Networks, Xiamen University, Xiamen 361102, China.

Abstract

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.

KEYWORDS:

c-SRC kinase CSK; castration-resistant prostate cancer; human prostate cancer tissue samples; mouse xenografts; siRNA screen

PMID:
26091350
PMCID:
PMC4673146
DOI:
10.18632/oncotarget.4279
[Indexed for MEDLINE]
Free PMC Article

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