Recent research has uncovered a surprising factor driving treatment resistance in advanced prostate cancer: extrachromosomal DNA (EcDNA). By using multi-omic data integration—analyzing DNA, RNA, epigenomic alterations, and 3D genome structure—scientists have revealed how EcDNA contributes to androgen receptor (AR) overexpression, genomic disorganization, and therapy resistance in metastatic castration-resistant prostate cancer (mCRPC).

Traditionally, AR dysregulation was thought to result from changes within the linear genome. This new study shows that in a subset of mCRPC cases, the AR gene is present on a circularized piece of DNA outside the chromosome. These EcDNA circles enable significantly higher AR copy numbers and elevated expression, which in turn fuel the tumor’s growth and reliance on androgen signaling. When exposed to standard androgen receptor inhibitors like enzalutamide and abiraterone, tumors with AR EcDNA often fail to respond or rapidly develop resistance.

In affected samples, the AR gene becomes physically separated from its usual genomic neighbors, enabling it to be overexpressed without the typical regulatory constraints. This amplified AR signaling drives aggressive tumor behavior and reduces the effectiveness of standard treatments.

The findings highlight the need for new therapeutic strategies. Emerging treatments might include AR degraders—drugs designed to break down the AR protein—and agents specifically targeting EcDNA.

In essence, this groundbreaking work shifts the paradigm of how we understand androgen receptor dysregulation. The identification of AR EcDNA as a key player in treatment resistance opens the door to innovative treatment options and provides a deeper understanding of the molecular complexities of advanced prostate cancer.

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