Characterizing Mechanisms of Resistance to Androgen Deprivation in Prostate Cancer
Abstract
Despite significant advances in the treatment, prostate cancer (PCa) remains a leading cause of cancer death among men. Androgen deprivation therapy (ADT)constitutes the main therapeutic option for patients with advanced PC. However, the major cause of death in men with metastatic prostate cancer involves progression to castration-resistant prostate cancer (CRPC). Characterizing mechanisms of resistance to ADT could enable the development of more effective therapeutic strategies. We performed a systematic genome-wide suppressor RNAi screen in the androgen-sensitive LNCaP cells, and identified genes whose silencing drives resistance to ADT in androgen-sensitive LNCaP cells, using next gen sequencing. shRNA-mediated-knock-down and CRISPR-mediated knock-out in vitro experiments, as well as in vivo PCa xenografts, confirmed a role for the top hit INPP5A as a gene whose silencing modulates resistance to ADT in prostate cancer, through a mechanisms only partially AR-dependent. INPP5A gene was found deleted in CRPC patients, as well as INPP5A mRNA levels reduced in CRPC patient-derived xenografts, supporting the idea that INPP5A may prove clinical relevance for patients with castration-resistant PCa.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 01, 2015
- Accession Number
- AD1001316
Entities
People
- Ginevra Botta
Organizations
- Dana–Farber Cancer Institute