Convergent evolution of complex structural variants drives therapy resistance in metastatic prostate cancer

Moreno-Rodriguez, T; Zhang, M; Lundberg, A; Shrestha, R; Sj&#246;str&#246;m, M; Pasam, A; Chan, J; Devereux, L; Foye, A; Zhu, X; Weinstein, AS; Trigos, AS; Wyatt, AW; Alumkal, JJ; Small, EJ; Aggarwal, R; Dehm, SM; Bootsma, ML; Zhao, SG; Lupien, M; Feng, FY; Sandhu, S; Quigley, DA

Author(s): Moreno-Rodriguez, T; Zhang, M; Lundberg, A; Shrestha, R; Sjöström, M; Pasam, A; Chan, J; Devereux, L; Foye, A; Zhu, X; Weinstein, AS; Trigos, AS; Wyatt, AW; Alumkal, JJ; Small, EJ; Aggarwal, R; Dehm, SM; Bootsma, ML; Zhao, SG; Lupien, M; Feng, FY; Sandhu, S; Quigley, DA;
Details: Publication Year 2026-04-15,Volume 27,Issue #1,Page 177
Journal Title: Genome Biology
Publication Type: Research article
Abstract: 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.
Publisher: BioMed Central
Keywords: Humans; Male; *Prostatic Neoplasms, Castration-Resistant/genetics/pathology/drug therapy; *Drug Resistance, Neoplasm/genetics; Receptors, Androgen/genetics; Neoplasm Metastasis; *Evolution, Molecular
Department(s): Laboratory Research; Medical Oncology
Publisher's Version: https://doi.org/10.1186/s13059-026-04074-2
Open Access at Publisher's Site: https://doi.org/10.1186/s13059-026-04074-2
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-04-28 05:52:37

Last Modified: 2026-06-04 11:59:38