Rewriting androgen-targeted therapy resistance with non-coding RNAs in prostate cancer treatment

Prostate cancer is one of the most prevalent forms of cancer among men, presenting unresolved challenges in treatment resistance. Despite the initial responses to androgen-targeted therapy, the mainstay treatment, patients inevitably develop adaptive resistance mechanisms, giving rise to the metastatic castration-resistant prostate cancer phenotype. Non-coding RNA (ncRNA) was initially considered the “dark matter” of the human genome due to the lack of evidence of their transcription and failure to encode proteins. However, thanks to the seminal discovery by Ambros and Ruvkun (Nobel Prize in Physiology or Medicine, 2024) and 30 years of progressive research, ncRNAs have emerged as indispensable regulatory elements in complex, multicellular life. Studies have demonstrated that ncRNAs play an indispensable regulatory role in prostate cancer development by rewiring oncogenic and tumor suppressor signaling pathways. This review summarizes the ncRNA-mediated molecular mechanisms involved in androgen-targeted therapy resistance. Moreover, the review discusses the potential clinical utility of ncRNAs as biomarkers and therapeutic targets to circumvent prostate cancer progression.