University of Arizona Cancer Center, Tucson, AZ 85724, USA; Department of Pathology, University of Arizona, Tucson, AZ 85724, USA.
University of Arizona Cancer Center, Tucson, AZ 85724, USA.
Cell Rep. 2018 Jan 30;22(5):1185-1199. doi: 10.1016/j.celrep.2018.01.022.
Approximately 30% of triple-negative breast cancers (TNBCs) exhibit functional loss of the RB tumor suppressor, suggesting a target for precision intervention. Here, we use drug screens to identify agents specifically antagonized by the retinoblastoma tumor suppressor (RB) using CDK4/6 inhibitors. A number of candidate RB-synthetic lethal small molecules were identified, including anti-helmenthics, chemotherapeutic agents, and small-molecule inhibitors targeting DNA-damage checkpoints (e.g., CHK) and chromosome segregation (e.g., PLK1). Counter-screens using isogenic TNBC tumor cell lines and cell panels with varying endogenous RB statuses confirmed that therapeutic effects were robust and selective for RB loss of function. By analyzing TNBC clinical specimens, RB-deficient tumors were found to express high levels of CHK1 and PLK1. Loss of RB specifically resulted in loss of checkpoint functions governing DNA replication, yielding increased drug sensitivity. Xenograft models demonstrated RB-selective efficacy of CHK inhibitors. This study supports the possibility of selectively targeting RB loss in the treatment of TNBC.
大约 30%的三阴性乳腺癌（TNBC）表现出 RB 肿瘤抑制因子的功能丧失，这表明它可能是精准干预的靶点。在这里，我们使用药物筛选来鉴定使用 CDK4/6 抑制剂特异性拮抗视网膜母细胞瘤肿瘤抑制因子（RB）的药物。确定了许多候选 RB 合成致死小分子，包括抗蠕虫药、化疗药物以及针对 DNA 损伤检查点（例如 CHK）和染色体分离（例如 PLK1）的小分子抑制剂。使用同基因 TNBC 肿瘤细胞系和具有不同内源性 RB 状态的细胞面板进行的反筛选证实，治疗效果对 RB 功能丧失是强大且具有选择性的。通过分析 TNBC 临床标本，发现 RB 缺陷型肿瘤表达高水平的 CHK1 和 PLK1。RB 的缺失特异性导致了控制 DNA 复制的检查点功能丧失，从而增加了药物敏感性。异种移植模型证明了 CHK 抑制剂对 RB 的选择性疗效。这项研究支持在治疗 TNBC 中选择性靶向 RB 缺失的可能性。
