A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer Journal Article

Authors: Lunardi, A.; Ala, U.; Epping, M. T.; Salmena, L.; Clohessy, J. G.; Webster, K. A.; Wang, G.; Mazzucchelli, R.; Bianconi, M.; Stack, E. C.; Lis, R.; Patnaik, A.; Cantley, L. C.; Bubley, G.; Cordon-Cardo, C.; Gerald, W. L.; Montironi, R.; Signoretti, S.; Loda, M.; Nardella, C.; Pandolfi, P. P.
Article Title: A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer
Abstract: Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten loss-driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed with deletion of either Trp53 or Zbtb7a together with Pten, leading to the development of castration-resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1, XIAP and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments. © 2013 Nature America, Inc. All rights reserved.
Keywords: signal transduction; controlled study; treatment failure; unclassified drug; human cell; androgen; nonhuman; antineoplastic agents; animal cell; mouse; animals; mice; animal tissue; apoptosis; models, biological; animal experiment; animal model; protein; drug evaluation, preclinical; cell line, tumor; mice, transgenic; prostate cancer; prostatic neoplasms; cancer genetics; dextran; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; pten phosphohydrolase; androgen antagonists; bicalutamide; dutasteride; orchiectomy; tumor growth; androgen deprivation therapy; androgens; castration resistant prostate cancer; phenylthiohydantoin; experimental model; x linked inhibitor of apoptosis; therapies, investigational; protein trp53; enzalutamide; steroid 5alpha reductase 1; translational medical research; charcoal; embelin; protein xaf1; protein zbtb7a
Journal Title: Nature Genetics
Volume: 45
Issue: 7
ISSN: 1061-4036
Publisher: Nature Publishing Group  
Date Published: 2013-07-01
Start Page: 747
End Page: 755
Language: English
DOI: 10.1038/ng.2650
PROVIDER: scopus
PUBMED: 23727860
PMCID: PMC3787876
Notes: --- - Cited By (since 1996):4 - "Export Date: 1 August 2013" - "CODEN: NGENE" - "Source: Scopus"
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  1. Guocan Wang
    5 Wang