Available online 11 April 2025

Under the selective pressure of treatment, prostate cancer cells express constitutively active androgen receptor (AR) variants. Whether AR variants mediate therapy resistance remains contested, because they are often coexpressed with abundant full-length AR. Therefore, we sought to determine how truncated variants shape AR chromatin occupancy and responses to treatments in both the presence and absence of full-length AR.

We used a cohort of patient-derived xenografts of metastatic prostate cancer with diverse AR alterations. Chromatin immunoprecipitation and RNA sequencing were used to compare the landscape of AR binding and transcriptomic features. We assessed responses to castration by castrating host mice and evaluated responses to bipolar androgen therapy by administering testosterone cypionate.

By profiling the AR cistrome, we identified a distinct group of tumours defined by ARv567es expression, a variant arising due to structural rearrangements of the AR gene. ARv567es-positive tumours also had a distinct epigenomic profile and altered transcriptional features, including loss of canonical AR-regulated gene signatures and elevated expression of AR-repressed genes. ARv567es-positive tumours were resistant to castration and bipolar androgen therapy. In tumours that coexpress full-length AR, this involves dampened transcriptional responses and disruption of the autoregulatory loop that modulates AR levels. Study limitations include the need for additional models of AR-driven prostate cancer.

The emergence of ARv567es via gene rearrangements causes transcriptional reprogramming and therapy resistance. This highlights ARv567es as a potential as a marker to guide treatment decisions.

Prostate cancer

Androgen receptor

Bipolar androgen therapy

Androgen deprivation therapy

Patient-derived xenograft

Chromatin immunoprecipitation

Cistrome

© 2025 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology.