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Selection for androgen receptor mutations in prostate cancers treated with androgen antagonist
M E Taplin1, G J Bubley, Y J Ko
1University of Massachusetts Cancer Center, Worcester 01655, USA.
Abstract:
The role of androgen receptor (AR) mutations in androgen-independent prostate cancer (PCa) was determined by examining AR transcripts and genes from a large series of bone marrow metastases. Mutations were found in 5 of 16 patients who received combined androgen blockade with the AR antagonist flutamide, and these mutant ARs were strongly stimulated by flutamide. In contrast, the single mutant AR found among 17 patients treated with androgen ablation monotherapy was not flutamide stimulated. Patients with flutamide-stimulated AR mutations responded to subsequent treatment with bicalutamide, an AR antagonist that blocks the mutant ARs. These findings demonstrate that AR mutations occur in response to strong selective pressure from flutamide treatment.
Insights
Androgen receptor (AR) mutations emerge in prostate cancer (PCa) under flutamide treatment pressure. These mutations can be targeted by bicalutamide, offering a new treatment avenue for advanced PCa.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Androgen receptor (AR) signaling is crucial for prostate cancer (PCa) growth.
- Treatment resistance, including androgen independence, remains a significant challenge in advanced PCa.
- The role of AR mutations in acquired resistance to anti-androgen therapies is not fully understood.
Purpose of the Study:
- To investigate the occurrence and functional impact of AR mutations in patients with advanced prostate cancer treated with anti-androgen therapies.
- To determine if AR mutations are selected for under specific treatment regimens.
- To assess the response of tumors with AR mutations to subsequent anti-androgen treatments.
Main Methods:
- Analysis of AR transcripts and genes from bone marrow metastases of prostate cancer patients.
- Genomic DNA and RNA extraction and sequencing.
- Functional assays to assess AR activity and drug response in vitro.
Main Results:
- AR mutations were identified in 5 out of 16 patients treated with combined androgen blockade including flutamide.
- These flutamide-stimulated AR mutations were not observed in patients treated with androgen ablation monotherapy.
- Patients with flutamide-stimulated AR mutations showed response to subsequent bicalutamide treatment.
Conclusions:
- Flutamide treatment exerts strong selective pressure for the emergence of AR mutations in advanced prostate cancer.
- AR mutations can confer resistance to flutamide but remain sensitive to bicalutamide.
- Targeting mutant ARs with specific antagonists like bicalutamide is a viable strategy for managing treatment-resistant prostate cancer.