AR intragenic deletions linked to androgen receptor splice variant expression and activity in models of prostate...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Castration-resistant prostate cancer (CRPCa) often reactivates the androgen receptor (AR) during androgen depletion therapy (ADT).
• Truncated AR variants, resulting from alternative splicing, are a key mechanism of ADT resistance in CRPCa.
• Previous work linked altered AR splicing in CRPCa cells to an intragenic tandem duplication within the AR gene.

Purpose of the Study:

• To investigate AR gene copy number imbalances and their potential link to AR gene rearrangements and splicing disruptions in CRPCa.
• To analyze AR gene structure in CRPCa models (LuCaP 86.2 and CWR-R1) to understand resistance mechanisms.

Main Methods:

• Analysis of AR gene copy number imbalances in prostate cancer (PCa) cell lines, xenografts, and clinical specimens.
• Deletion-spanning PCR to identify AR gene deletions in the LuCaP 86.2 xenograft model.
• Targeted resequencing of the AR gene in CWR-R1 cells to detect structural alterations.

Main Results:

• A 8579-bp deletion of AR exons 5, 6, and 7 was identified in the LuCaP 86.2 xenograft, explaining the AR v567es variant synthesis.
• A 48-kb deletion in AR intron 1 was discovered in CWR-R1 cells, associated with AR-V7/AR3 variant expression and androgen-independent growth.
• Complex AR gene copy number imbalances and structural alterations correlate with splicing disruptions and enhanced AR activity in CRPCa.

Conclusions:

• Structural alterations within the AR gene are directly linked to stable, gain-of-function splicing alterations in CRPCa.
• These AR gene rearrangements contribute to the development of castration resistance and androgen-independent tumor growth.
• Understanding these genetic mechanisms is crucial for developing targeted therapies for advanced prostate cancer.