Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer.
Targeting the Vulnerability of RB Tumor Suppressor Loss in Triple-Negative Breast Cancer.
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DOI：
10.1016/j.celrep.2018.01.022
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发表时间：
2018-01-30
期刊：
影响因子：
8.8
通讯作者：
Knudsen ES
中科院分区：
文献类型：
--
作者：
Witkiewicz AK;Chung S;Brough R;Vail P;Franco J;Lord CJ;Knudsen ES
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，这表明精确干预的目标。在这里，我们使用药物筛选，以确定药物特异性拮抗视网膜母细胞瘤肿瘤抑制（RB）使用CDK 4/6抑制剂。鉴定了许多候选的RB合成致死小分子，包括抗蠕虫药、化疗剂和靶向DNA损伤检查点的小分子抑制剂（例如，CHK）和染色体分离（例如，PLK 1）。使用具有不同内源性RB状态的同基因TNBC肿瘤细胞系和细胞组的反筛选证实了治疗效果对于RB功能丧失是稳健的和选择性的。通过分析TNBC临床标本，发现RB缺陷型肿瘤表达高水平的CHK 1和PLK 1。RB的丢失特别导致控制DNA复制的检查点功能的丢失，从而增加药物敏感性。异种移植模型证明了CHK抑制剂的RB选择性功效。该研究支持在TNBC治疗中选择性靶向RB损失的可能性。Witkiewicz等人证明，RB肿瘤抑制因子的活化状态是TNBC模型中选定靶向治疗的关键决定因素。RB的损失产生复制和染色体分离应力的选择性脆弱性。靶向CHK和PLK的药物在RB缺陷型肿瘤中具有更高的疗效。
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. Witkiewicz et al. demonstrate that the activation state of the RB tumor suppressor is a critical determinant for selected targeted therapies in models of TNBC. Loss of RB yields a selective vulnerability to replication and chromosome segregation stress. Drugs targeting CHK and PLK have increased efficacy in RB-deficient tumors.
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