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.
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Lunardi
authors.forename: Ugo
authors.initials: U
authors.lastname: Ala
authors.forename: Mirjam T
authors.initials: MT
authors.lastname: Epping
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salmena
authors.forename: John G
authors.initials: JG
authors.lastname: Clohessy
authors.forename: Kaitlyn A
authors.initials: KA
authors.lastname: Webster
authors.forename: Guocan
authors.initials: G
authors.lastname: Wang
authors.forename: Roberta
authors.initials: R
authors.lastname: Mazzucchelli
authors.forename: Maristella
authors.initials: M
authors.lastname: Bianconi
authors.forename: Edward C
authors.initials: EC
authors.lastname: Stack
authors.forename: Rosina
authors.initials: R
authors.lastname: Lis
authors.forename: Akash
authors.initials: A
authors.lastname: Patnaik
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Glenn
authors.initials: G
authors.lastname: Bubley
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: William L
authors.initials: WL
authors.lastname: Gerald
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Montironi
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: Caterina
authors.initials: C
authors.lastname: Nardella
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use*; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009570:Nitriles; D009919:Orchiectomy; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D035703:Therapies, Investigational; D057170:Translational Research, Biomedical / Q000379:methods; D017211:Treatment Failure
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D010669:Phenylthiohydantoin; C540278:enzalutamide; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse