The recent introduction of novel androgen receptor (AR)-directed drugs for treatment of castration-resistant prostate cancer (CRPC) has increased the prevalence of aggressive AR-negative pathologies in the clinic. These neuroendocrine (CRPC-NE) and double negative (CRPC-DN) tumours are now present in a third of CPRC patients, and are lethal. While we know that these tumours arise from transdifferentiation of AR-positive adenocarcinomas, there is currently little investigation into the precursors of AR-negative tumours in the early stages of disease progression.
We investigated the origins of CRPC-NE and CRPC-DN using mouse and patient-derived models of prostate cancer. In mouse models, we compared the response of prostate tumours initiated by deletion of Pten or co-deletion of Pten and Trp53 in luminal cells, which were treated with the potent AR-directed inhibitor abiraterone. We found that mouse adenocarcinomas with Pten deletion were abiraterone responsive, while adenocarcinomas with Pten and Trp53 deletion were non-responsive and progressed to CRPC-NE and CRPC-DN1. Notably, prior to development of AR-negative subtypes, adenocarcinomas of Pten and Trp53 deleted mice displayed a sub-pathology called focal neuroendocrine differentiation. This implies combined loss of PTEN and TP53 in luminal cells permits phenotypic plasticity and the development of AR-negative pathologies. Furthermore, focal neuroendocrine differentiation is also present in a subset of human patients and can be detected as early as initial diagnosis. Indeed, we have established patient-derived xenografts from these lesions, as well as of tumours spanning overt AR-negative subtypes, and these xenografts display similar properties to that observed in mice.
Taken together, these findings suggest adenocarcinomas with distinct sub-pathologies can be the precursors to AR-negative subtypes of CRPC. Furthermore, we have established unique patient-derived xenografts for studying the progression to AR-negative subtypes. Future work will determine the prognostic utility of detecting focal neuroendocrine differentiation at diagnosis and evaluate improved therapeutic strategies for targeting aggressive AR-negative tumours.