Dr. Alexander Wyatt and Team Map How Advanced Prostate Cancers Rewire the Androgen Receptor
Advanced prostate cancer is usually treated by blocking male-hormone signaling through the androgen receptor (AR). Over time, many cancers learn to bypass these therapies by rewiring the AR gene itself.
A new study published in Annals of Oncology (Virtanen et al., 2025) led by Dr. Alexander Wyatt of the Vancouver Prostate Centre (VPC), in collaboration with Matti Annala’s group at the University of Tampere, Finland, used a comprehensive liquid biopsy approach, studying tumour DNA fragments in blood, to map exactly how the AR gene changes in metastatic castration-resistant prostate cancer (mCRPC), and which changes matter most for treatment response.
Study Details
Dr. Wyatt’s lab analyzed blood samples from 1,751 patients with mCRPC across multiple international clinical trials and a BC-based biobank, using a sequencing approach designed to study the AR gene in high detail. Key findings include:
- AR gene changes are common but diverse: 84% of mCRPC patients had AR alterations to bypass hormone-blocking drugs.
- Different types of AR alterations:
- Extra copies of the AR gene (“turning the volume up”)
- Small mutations that make drugs bind less effectively
- Chromosome breaks and re-joins that create abnormal AR proteins
- A key resistance marker ~ ALTR4:
This rearrangement removes the part of the AR protein that many drugs target. ALTR4 became more common after AR-targeting therapy and was linked to poorer outcomes.
- No AR change doesn’t mean treatment won’t work: About 1 in 6 men had no detectable AR DNA alteration in blood, yet many still benefited from standard AR-targeted therapy.
Predictable Resistance Patterns
The study also revealed that the type of AR change is linked with other molecular features of each patient’s cancer. Tumours with changes in the Wnt pathway, a key growth-control system, showed distinct patterns of AR copy number increases, suggesting that cancers may follow predictable trajectories of treatment resistance.
Implications for Patient Care
Dr. Wyatt and collaborators provide a practical “clinical hierarchy” of AR genotypes, showing that some alterations, like ALTR4, are strong biomarkers of resistance, while absence of detectable AR changes doesn’t necessarily indicate AR-independence. These insights will help:
- Refine blood-based biomarker testing
- Guide the development of next-generation AR-targeted therapies
- Improve treatment selection and sequencing for people with advanced prostate cancer
This study marks a significant advance in understanding how prostate cancers adapt to therapy and how clinicians can anticipate and counteract treatment resistance, led by the expertise of Dr. Alexander Wyatt and the VPC team.