title: Downregulation of c-SRC kinase CSK promotes castration resistant prostate cancer and pinpoints a novel disease subclass.
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.
authors.affiliation: Tumor Initiation & Maintenance Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.|Functional Genomics Core, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Yang
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada V6H 3Z6.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: San Diego Center for Systems Biology, La Jolla, CA 92037, USA.|Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Loguercio
authors.affiliation: Tumor Analysis Core, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Zharkikh
authors.affiliation: Functional Genomics Core, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Aza-Blanc
authors.affiliation: Vancouver Prostate Centre, Vancouver, BC, Canada V6H 3Z6.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.affiliation: Tumor Initiation & Maintenance Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.|San Diego Center for Systems Biology, La Jolla, CA 92037, USA.|School of Pharmaceutical Sciences & Center for Stress Signaling Networks, Xiamen University, Xiamen 361102, China.
authors.forename: Dieter A
authors.initials: DA
authors.lastname: Wolf
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D015536:Down-Regulation; D057809:HEK293 Cells; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D064129:Prostatic Neoplasms, Castration-Resistant / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human
keywords: c-SRC kinase CSK; castration-resistant prostate cancer; human prostate cancer tissue samples; mouse xenografts; siRNA screen