Alterations of TP53 mediate resistance to abiraterone in castration-resistant prostate cancer

Prostate cancer remains the second-leading cause of cancer death in men. The first line treatment for advanced prostate cancer is hormone deprivation therapy (ADT), which although it is initially effective, usually leads to progression to more aggressive and often lethal castration resistant prostate cancer (CRPC). Nonetheless, CRPC remains dependent on androgen receptor (AR) signaling through various mechanisms. Therefore, drugs that target androgen synthesis or AR signaling, such as abiraterone acetate and enzalutamide, have been employed as second line therapy. Despite the fact that both drugs improve the overall survival for CRPC patients, neither of them is curative, suggesting intrinsic or acquired resistance. Here we have focused on elucidating resistance mechanisms for abiraterone acetate, an inhibitor of androgen biosynthesis, using preclinical analyses of relevant genetically engineered mouse models (GEMMs). Given the high frequency of co-alteration in PTEN and p53 in mCRPC, we generated conditional GEMMs based on deletion of either PTEN alone or PTEN plus p53 to obtain the NP and NPp53 GEMMs, respectively. Both NP and NPp53 mice develop CRPC, and cross-species gene set enrichment analysis (GSEA) suggests that they have molecular programs that are well-conserved with human CRPC. In preclinical studies, we find that the NP mice are highly responsive to tumor inhibition by abiraterone, whereas the NPp53 mice do not respond. In fact, the NPp53 mice display a marked acceleration of tumor progression following abiraterone treatment. The disparate phenotypic responses of the NP and NPp53 mice to abiraterone are evident by analyses of their tumor histology, immunohistochemical staining, as well as the change in tumor volume by MRI imaging. We further validated the results in a genetically modified human prostate cancer cell line. In particular, a xenograft model based on 22RV1 cells that are depleted for both PTEN and p53 also displayed an acceleration of the tumor phenotype following abiraterone treatment. Notably, expression profiling of the abiraterone- or vehicle-treated 'responder' NP tumors versus 'non-responder' NPp53 tumors identified a unique set of cancer driver genes that are enriched for genes found in human neuroendocrine prostate cancer (NEPC). These findings were confirmed by immunohistochemistry, which demonstrated a significant increase in synaptophysin-expressing cells in CRPC in the NPp53 mice but not the NP mice. Our findings suggest that loss of p53 in the context of PTEN deletion promotes resistance to abiraterone while CRPC in the NPp53 mice partially resemble human NEPC. Given the high prevalence of co-alteration of PTEN and p53 in advanced human mCRPC, and observed occurrence of treatment induced NEPC-like phenotypes observed following treatment with AR targeting agents in patients, our finding suggest that abiraterone may not be suitable for patients with alterations in both PTEN and p53.