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

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.