Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA.
Cell Rep. 2020 May 26;31(8):107669. doi: 10.1016/j.celrep.2020.107669.
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.
前列腺癌（PCs）失去强效肿瘤抑制因子 TP53 和 RB1 后，预后较差。TP53 和 RB1 还影响细胞可塑性，并且经常在具有神经内分泌（NE）分化的 PCs 中丢失。迫切需要针对这些侵袭性变异 PCs 的治疗策略。通过对 410 个转移性活检样本进行深度基因组分析，我们确定了联合 TP53 和 RB1 缺失与 PC 表型之间的关系。值得注意的是，40%的 TP53/RB1 缺陷肿瘤被归类为 AR 活性腺癌，表明 NE 分化不是 TP53/RB1 失活的必然结果。反映 TP53/RB1 缺失的基因表达特征与对 AR 拮抗剂反应减弱和生存时间缩短有关。这些肿瘤具有较高的增殖率和证据表明 DNA 修复过程增加。虽然缺乏 TP53/RB1 的肿瘤细胞对所有测试的单一药物治疗均具有高度耐药性，但发现 PARP 和 ATR 抑制的联合使用可产生显著反应，反映出由于复制应激而产生的一种临床上可利用的脆弱性。
