br Introduction Prostate cancer strikes one in

Introduction Prostate cancer strikes one in six men and is the second leading cause of cancer-related deaths in men after lung cancer in the United States. Prostate cancer arises mainly from prostatic intraepithelial neoplasia (PIN), a precursor lesion that ultimately progresses to adenocarcinoma and systemic VE-822 (DeMarzo et al., 2003). Conventional androgen deprivation therapy (ADT) by surgical and/or chemical castration remains the standard of care for metastatic prostate cancer. Unfortunately, these prostate cancers invariably develop resistance to ADT and progress to a more aggressive castration-resistant prostate cancer (CRPC) within 18–24months. Chemotherapy with docetaxel (Petrylak et al., 2004) or its derivative carbazitaxel after development of docetaxel resistance (de Bono et al., 2010) offers a 3–4months survival benefit for CRPC patients. The discovery that persistent androgen receptor (AR) signaling plays a crucial role in the progression of CRPC leads to “second generation” ADT modalities (Chen et al., 2004; Tran et al., 2009), such as the Food and Drug Administration-approved androgen synthesis blocker abiraterone (2011, FDA) and the second generation of AR signaling inhibitor enzalutamide (formerly MDV3100) (2012, FDA), which have demonstrated efficacy against chemotherapy-resistant CRPC with median increase in survival of 4–5months (de Bono et al., 2011; Ryan et al., 2013; Scher et al., 2010, 2012). However, nearly all CRPC patients inevitably develop acquired resistance to the second generation anti-AR signaling axis treatments within ~6–12months (Claessens et al., 2014). Significantly, approximately 20 to 40% of CRPC patients do not initially respond to abiraterone or enzalutamide with respect to prostate-specific antigen (PSA) levels (de Bono et al., 2011; Ryan et al., 2013; Scher et al., 2010, 2012), suggesting a subset of CRPC possesses de novo/innate resistance to next-generation anti-AR axis therapies. Therefore, understanding the molecular mechanisms underlying the innate/acquired resistance to current anti-AR axis therapies has important clinical implications towards a better stratification of CRPC patients, rational designing of innovative and cost-effective personalized therapeutic strategies for them, as well as the discovery of novel therapeutics for overcoming resistance. Beside the AR signaling axis, accumulating evidence suggests that important fundamental genetic alterations, such as loss of tumor suppressor genes PTEN and/or TP53, might play a crucial role in the development of CRPC (Chen et al., 2005; Lunardi et al., 2013; Wang et al., 2014). Recent advances in whole-genome/exome sequencing analyses reveal that PTEN and TP53 are often co-deleted or co-mutated in lethal CRPC (Grasso et al., 2012). A systematic and multi-institutional study of metastatic CRPC specimens has shown that 60 cases (40%) have PTEN mutations, 75 cases (50%) have TP53 mutations, and 34 cases (22.7%) have co-occurrence of PTEN and TP53 mutations in the 150 cases of metastatic CRPC (Robinson et al., 2015). Importantly, tracking the clonal origin of lethal prostate cancer through patient samples collected during tumor progression and at the time of death identified that the lethal metastatic clone arose from primary prostate cancer cells carrying PTEN deletion and mutant p53 (Haffner et al., 2013). Systems bioinformatics analyses estimate that prostate cancers with combined loss of PTEN and TP53 make up 11% of highly aggressive prostate cancers and they bestow the worst survival outcome for patients (Markert et al., 2011). Strikingly, 4 out of 6 CRPC patients-derived prostate cancer organoid lines carry co-mutations of PTEN/TP53 (Gao et al., 2014). In support of the clinical findings that co-deletion/−mutation of PTEN/TP53 in prostate epithelial cells plays a causal role in prostate tumorigenesis, mouse genetic studies suggest that Pten deletion in prostate epithelial cells primarily initiates PIN, whereas p53 loss in prostate epithelial cells is not sufficient to cause any distinguishable morphological phenotypes in vivo. However, double deletion of Pten and p53 in murine prostate epithelial cells leads to invasive prostate cancer (Chen et al., 2005; Wang et al., 2014) which develops into CRPC with innate or de novo resistance to conventional ADT in vivo (Lunardi et al., 2013). Thus, utilizing the Pten−/−-deficient CRPC model that recapitulates the salient features of a subset of human CRPC to explore effective and selective means of killing prostate cancer cells in vivo is a critical step to develop novel therapeutic strategies to successfully treat the CRPC patients harboring PTEN/TP53 mutations.