Functionally Characterizing the Noncoding Genome of Metastatic Prostate Cancer to Identify Therapeutic Vulnerabilities
Abstract
Prostate cancer (PCa) is dependent on the androgen receptor (AR) at all stages of the disease. Given this critical role, inhibiting AR function is the standard-of-care to treat advanced PCa. However, while treatment is initially effective, resistance to treatment inevitably occurs resulting in lethal metastatic castrate-resistant PCa (mCRPC). Importantly, the vast majority of mCRPC tumors still remain fully dependent on AR signalling. Yet when the cancer adapts to low circulating androgens the AR program is dramatically altered. We recently reported that during progression to castration resistance, AR binding sites (ARBS) on the DNA are heavily reprogrammed and gain a set of ~17,000 new binding sites. These gained metastatic AR binding sites (mARBS) reactivate a latent prostate developmental program. Notably, the massive change in the AR cistrome -the universe of all AR binding sites in the genome- is highly recurrent across patients, suggesting that this common mechanism that represents a universal feature of castration resistance in mCRPC tumors. Intriguingly, we observed that these gained ARBS are highly mutated and may potentially alter AR-mediated transcription to drive tumour growth in mCRPC. Yet while we can readily identify these gained mARBS and their mutations, the specific subset of sites that are critical to the metastatic process remains unknown. In addition, it remains elusive which biological pathways are selectively driving metastatic outgrowth in this setting. Our published work provides a clear foundation for studying the mCRPC-specific AR cistrome. We strongly believe that our results will reveal important insights into mechanisms of progressive metastatic PCa and will provide new avenues of how treatment can be improved for these patients. We propose that a subset of metastatic ARBS are responsible for driving the growth of CRPC and a fraction of these sites possess gain-of-function somatic mutations.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2022
- Accession Number
- AD1176304
Entities
People
- Matthew L Freedman
Organizations
- Dana–Farber Cancer Institute