Transcriptional and epigenetic reprogramming, lineage plasticity and therapy resistance in prostate cancer.

Prostate cancer is the most commonly diagnosed and the second-leading cause of cancer-related mortality in men worldwide, especially in Western counties. Therapeutic resistance of prostate cancer remains a major challenge in modern oncology, necessitating new scientific understanding of the disease and devising new targeting strategies. This review examines the intricate relationship between transcriptional and epigenetic reprogramming, lineage plasticity, and therapeutic resistance in prostate cancer. Prostate cancer cells can adapt and resist various treatment modalities, including androgen deprivation therapy (ADT) and next-generation androgen receptor (AR) signaling inhibitors (ARSI), through transcriptional reprogramming and epigenetic modifications. Lineage plasticity, the ability of cells to alter their cellular identities, further drives treatment resistance. Moreover, cancer cells can adjust their gene expression profiles to evade therapy by activating key transcription factors and epigenetic regulatory mechanisms such as DNA methylation, histone modification, and non-coding RNA expression. The article concludes by discussing new therapeutic strategies targeting these reprogramming and plasticity mechanisms, emphasizing the importance of combination therapy and precision medicine in developing more effective treatments for advanced prostate cancer.