期刊
CELL REPORTS
卷 31, 期 8, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.107669
关键词
-
类别
资金
- Prostate Cancer Foundation
- Stand Up to Cancer Prostate Cancer Dream Team research grant
- American Association for Cancer Research [SU2C-AACR-DT0712]
- NCI Cancer Center Support grant [P30CA015704]
- Pacific Northwest Prostate Cancer SPORE [P50CA97186, P01CA163227, R50CA221836, W81XWH-18-1-0347, W81XWH-18-1-0354]
- CDMRP [W81XWH-16-1-0206, W81XWH-15-1-0535]
Prostate cancers (PCs) with loss of the potent tumor suppressors TP53 and RB1 exhibit poor outcomes. TP53 and RB1 also influence cell plasticity and are frequently lost in PCs with neuroendocrine (NE) differentiation. Therapeutic strategies that address these aggressive variant PCs are urgently needed. Using deep genomic profiling of 410 metastatic biopsies, we determine the relationships between combined TP53 and RB1 loss and PC phenotypes. Notably, 40% of TP53/RB1-deficient tumors are classified as AR-active adenocarcinomas, indicating that NE differentiation is not an obligate consequence of TP53/RB1 inactivation. A gene expression signature reflecting TP53/RB1 loss is associated with diminished responses to AR antagonists and reduced survival. These tumors exhibit high proliferation rates and evidence of elevated DNA repair processes. While tumor cells lacking TP53/RB1 are highly resistant to all single-agent therapeutics tested, the combination of PARP and ATR inhibition is found to produce significant responses, reflecting a clinically exploitable vulnerability resulting from replication stress.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据