Convergent evolution of complex structural variants drives therapy resistance in metastatic prostate cancer
BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors
- Lisa Devereux (ORCID: https://orcid.org/0000-0003-2435-5888)
- Mathieu Lupien (ORCID: https://orcid.org/0000-0003-0929-9478)
- Alana S. Weinstein (ORCID: https://orcid.org/0000-0002-1563-9072)
- Arian Lundberg (ORCID: https://orcid.org/0000-0002-6630-2787)
- Raunak Shrestha (ORCID: https://orcid.org/0000-0002-1144-1413)
- Thaidy Moreno-Rodriguez (ORCID: https://orcid.org/0000-0003-3588-3889)
- Martin Sjöström (ORCID: https://orcid.org/0000-0002-2629-9966)
- Joshi J. Alumkal (ORCID: https://orcid.org/0000-0003-1278-0166)
- Alexander W. Wyatt (ORCID: https://orcid.org/0000-0003-2399-0329)
- Shahneen Kaur Sandhu (ORCID: https://orcid.org/0000-0002-8660-4475)
- Adam Foye (ORCID: https://orcid.org/0000-0002-9910-9836)
- Scott M. Dehm (ORCID: https://orcid.org/0000-0002-7827-5579)
- Joanna Chan (ORCID: https://orcid.org/0000-0002-0371-1786)
- Matthew L. Bootsma (ORCID: https://orcid.org/0000-0003-0879-5066)
- M ZHANG
- Anupama Pasam
- Xiaolin Zhu
- Felix Y. Feng
- David A. Quigley
- Shuang G. Zhao
- Anna S. Trigos
- Rahul Aggarwal
- Eric J. Small
Institutions
- Ontario Institute for Cancer Research (CA)
- University of Minnesota (US)
- University of Wisconsin–Madison (US)
- University of British Columbia (CA)
- Emory University (US)
- The University of Melbourne (AU)
- University of California, San Francisco (US)
- University of Toronto (CA)
- University of Michigan (US)
- Peter MacCallum Cancer Centre (AU)
- Princess Margaret Cancer Centre (CA)
- University of Wisconsin Carbone Cancer Center (US)
- University of California San Francisco Medical Center (US)
- Canada's Michael Smith Genome Sciences Centre (CA)
- University of Minnesota Medical Center (US)
- William S. Middleton Memorial Veterans Hospital (US)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
Publication Details
- Journal
- Genome biology
- Published
- 2026-04-15
- DOI
- https://doi.org/10.1186/s13059-026-04074-2
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00