Androgen receptor amplification confers castration-resistance in matched patient-derived models of primary and metastatic prostate cancer

The reliance of prostate cancer on the androgen receptor (AR) underscores the initial response to AR-directed treatments, and the emergence of drug resistance due to the reactivation of AR activity. Recently, non-coding genomic amplifications of an AR enhancer were identified as common mechanisms of resistance to AR-directed therapies, prompting the need to identify alternative treatments for these patients. Here we present new, matched patient-derived models that chart the progression from high-risk, castrate-sensitive disease to castration-resistant prostate cancer with an amplified AR enhancer. We established serially transplantable patient-derived xenografts from a treatment-naive primary tumour and castrate-resistant spinal metastasis from the same patient. Whole genome sequencing showed that alterations associated with poor prognosis, such as TP53 and PTEN loss, were present before androgen deprivation therapy, followed by co-amplification of the AR gene and enhancer after the development of metastatic CRPC. The AR amplification was associated with castration-resistance, high AR and AR-V7 expression in castrate conditions, and resistance to apalutamide and enzalutamide in vivo. Despite the resistance to AR-directed treatments, there was a partial response to BET inhibition. Altogether, these matched PDXs provide new models to identify potential treatments that target the over-abundance of AR in tumours with AR enhancer amplifications.