Targeted therapy prolongs the lives of men with metastatic castration-resistant prostate cancer (mCRPC) but mCRPC is ultimately lethal. DNA copy gains that amplify the Androgen Receptor (AR) gene locus are a key driver of resistance to targeted therapy in mCRPC. Our group has recently shown that extra-chromosomal DNA (ecDNA) frequently drives this amplification. We hypothesized that ecDNA and other complex structural variants (cSVs) also affect other established drivers of therapy resistance in mCRPC and continue to evolve over time. To test this hypothesis, we reconstructed cSV profiles in 193 mCRPC tumors using whole genome and transcriptome sequencing, with matched Hi-C data for 77 tumors.
We identify ecDNA in more than half of mCRPC biopsies and show it frequently amplifies driver genes such as AR and MYC and their non-coding enhancers. The presence of ecDNA is significantly associated with whole genome doubling, chromothripsis, and inactivating TP53 alterations. Deep sequencing analysis of 53 rapid autopsy samples shows cSVs amplifying AR can arise independently within distinct tumors in a single patient. Phylogenetic analysis of tumor evolution implicates this cSV as an early event during metastatic spread. Additionally, a paired analysis of mCRPC samples as patients developed resistance to AR pathway inhibitor (ARPI) therapy demonstrates cSVs evolve in response to ARPI and can be detected in both tumor tissue and circulating tumor DNA.
We conclude that cSVs, particularly ecDNA, are a pervasive contributor to intra-patient heterogeneity in late-stage mCRPC and a key driver of targeted therapy resistance.
Genome biology. 2026 Apr 15 [Epub ahead of print]
Thaidy Moreno-Rodriguez, Meng Zhang, Arian Lundberg, Raunak Shrestha, Martin Sjöström, Anupama Pasam, Joanna Chan, Lisa Devereux, Adam Foye, Xiaolin Zhu, Alana S Weinstein, Anna S Trigos, Alexander W Wyatt, Joshi J Alumkal, Eric J Small, Rahul Aggarwal, Scott M Dehm, Matthew L Bootsma, Shuang G Zhao, Mathieu Lupien, Felix Y Feng, Shahneen Sandhu, David A Quigley
Department of Urology, UCSF, San Francisco, CA, USA., Department of Radiation Oncology, UCSF, San Francisco, CA, USA., Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Department of Oncology, Sir Peter MacCallum, University of Melbourne, Melbourne, VIC, Australia., Division of Hematology and Oncology, Department of Medicine, UCSF, San Francisco, CA, USA., Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA., Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA., Department of Human Oncology, University of Wisconsin, Madison, WI, USA., Princess Margaret Cancer Centre, Toronto, ON, Canada., Department of Urology, UCSF, San Francisco, CA, USA. .