AR mRNA stability is increased with AR-antagonist resistance via 3'UTR variants

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Advanced prostate cancer relies on the androgen receptor (AR) for growth.
• Resistance to AR antagonists like bicalutamide and enzalutamide is a major clinical challenge.
• Mechanisms of AR antagonist resistance, including AR upregulation and mutations, are not fully understood.

Purpose of the Study:

• To investigate novel mechanisms of AR antagonist resistance in prostate cancer.
• To identify and characterize new AR mRNA variants in resistant prostate cancer cells.
• To assess the clinical relevance of identified AR variants in patient samples.

Main Methods:

• Development of LNCaP and VCaP cell lines with acquired resistance to bicalutamide and enzalutamide.
• RNA sequencing (RNA-seq) to analyze AR mRNA transcripts in resistant cells.
• Actinomycin D and luciferase fusion assays to determine mRNA stability.
• Detection of AR variants in serum samples from prostate cancer patients.

Main Results:

• Resistant cells exhibited new AR mRNA variants in the 3' untranslated region (UTR), increasing with antagonist treatment and hormonal starvation.
• A 3 kb deletion within the 6.7 kb AR 3'UTR was observed in approximately 20% of AR transcripts.
• The shorter AR mRNA variant demonstrated increased stability in resistant cell lines.
• This AR 3'UTR variant was detectable in patient sera, with levels correlating with increasing Gleason grade.

Conclusions:

• A shorter, more stable AR 3'UTR mRNA variant is associated with acquired resistance to AR antagonists in prostate cancer.
• This variant may represent a survival adaptation, enabling sustained AR expression under low hormone or antagonist treatment conditions.
• The presence and level of this AR 3'UTR variant in patient sera suggest its potential as a biomarker for prostate cancer progression.