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

• Published in: Nature genetics Vol. 45; no. 7; pp. 747 - 755
• Main Authors: Lunardi, Andrea, Ala, Ugo, Epping, Mirjam T, Salmena, Leonardo, Clohessy, John G, Webster, Kaitlyn A, Wang, Guocan, Mazzucchelli, Roberta, Bianconi, Maristella, Stack, Edward C, Lis, Rosina, Patnaik, Akash, Cantley, Lewis C, Bubley, Glenn, Cordon-Cardo, Carlos, Gerald, William L, Montironi, Rodolfo, Signoretti, Sabina, Loda, Massimo, Nardella, Caterina, Pandolfi, Pier Paolo
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2013; Nature Publishing Group
• Subjects: 631/208/2489; Agriculture; Androgen Antagonists - therapeutic use; Androgen suppression therapy; Androgens; Androgens - metabolism; Animal Genetics and Genomics; Animals; Antineoplastic Agents - therapeutic use; Apoptosis; Biomarkers; Biomedicine; Cancer Research; Cancer therapies; Cancer treatment; Care and treatment; Cell Line, Tumor; Development and progression; Drug Evaluation, Preclinical; Gene Function; Genetic aspects; Health aspects; Human Genetics; Humans; Hypotheses; Integrated approach; Male; Medical research; Medical schools; Mice; Mice, Transgenic; Models, Biological; NMR; Nuclear magnetic resonance; Orchiectomy; Pathology; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - therapeutic use; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Prostatic Neoplasms - therapy; PTEN Phosphohydrolase - genetics; Rodents; Signal Transduction - drug effects; Signal Transduction - genetics; Therapies, Investigational; Translational Medical Research - methods; Treatment Failure; Tumors; United States
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.2650

Pier Paolo Pandolfi and colleagues report that compound loss of Pten with Zbtb7a or Trp53 leads to de novo resistance to androgen deprivation therapy in prostate cancer. Integrative analysis of mouse and human data in a co-clinical approach identified XIAP and SRD5A1 inhibitors as potential therapies for castration-resistant prostate cancer. 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.