Genetic and epigenetic mechanisms underlying treatment-induced neuroendocrine prostate cancer

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer (CRPC).
• Its incidence has risen due to androgen receptor pathway inhibitors (ARPi) in advanced prostate cancer (PCa).
• t-NEPC exhibits distinct epigenetic programs compared to CRPC, despite conserved genomic alterations.

Purpose of the Study:

• To review the genetic drivers of t-NEPC.
• To comprehensively examine 2D and 3D chromatin alterations during neuroendocrine transformation (NET) in PCa.
• To identify key molecular regulators of these epigenetic programs.

Main Methods:

• Review of genetic drivers in t-NEPC.
• Comprehensive review of 2D and 3D chromatin alterations (DNA methylation, histone modifications, chromatin accessibility, 3D organization) during PCa NET.
• Review of molecular regulators including transcription factors and chromatin modifiers.

Main Results:

• Genomic alterations are largely conserved between CRPC and t-NEPC.
• Epigenetic programs are markedly distinct, involving significant chromatin alterations.
• Key molecular regulators, including transcription factors and chromatin modifiers, orchestrate these epigenetic changes.

Conclusions:

• Epigenetic reprogramming is a critical mechanism underlying the neuroendocrine transformation of prostate cancer.
• A mixed model of clonal selection and transformation likely drives NEPC progression.
• Understanding these epigenetic mechanisms is crucial for developing new therapeutic strategies against t-NEPC.