A single nucleotide variant of human PARP1 determines response to PARP inhibitors
A single nucleotide variant of human PARP1 determines response to PARP inhibitors
复制标题
人类PARP1的单核苷酸变异决定了对PARP抑制剂的反应
DOI：
10.1038/s41698-020-0113-2
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发表时间：
2020-04-27
影响因子：
7.9
通讯作者：
Efroni, Sol
中科院分区：
文献类型：
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作者：
Cashman, Rivki;Zilberberg, Alona;Efroni, Sol
新型抗癌药物和创新治疗方法的推出给癌症患者带来了巨大的希望，但也迫切需要将药物与适合的患者相匹配，因为某些对一个患者有利的药物实际上可能会伤害其他患者。新开发的聚ADP核糖聚合酶（PARP）抑制剂（PARPis）是一组临床上用于多种适应症的药理酶抑制剂。多种癌症往往依赖于 PARP，这使得 PARP 成为癌症治疗的有吸引力的靶点。具体来说，PARPi通常用于BRCA相关乳腺癌患者，因为未修复的单链断裂会转化为双链断裂，而BRCA相关肿瘤无法通过同源重组修复它们，因此PARPi通过一种称为“合成致死”的机制导致肿瘤细胞死亡。不幸的是，并非所有患者都对 PARPi 做出反应，目前无法预测谁会或不会做出反应。在这里，我们提出了一种特定的基因组标记，它反映了人类 PARP1 的单核苷酸多态性，并在体外与所有适应症中对 PARPi 的反应相关。此外，我们报告该 SNP 与重塑 mRNA 和 mRNA 水平相关，并影响最终的蛋白质结构以暴露新的结合位点，同时隐藏其他结合位点。因此，SNP 的状态对于患者的护理至关重要，因为它将对 PARPi 的反应与所携带的 PARP1-SNP 相关联。
The introduction of novel cancer drugs and innovative treatments brings great hope for cancer patients, but also an urgent need to match drugs to suitable patients, since certain drugs that benefit one patient may actually harm others. The newly developed poly-ADP ribose polymerase (PARP) inhibitors (PARPis) are a group of pharmacological enzyme inhibitors used clinically for multiple indications. Several forms of cancer tend to be PARP dependent, making PARP an attractive target for cancer therapy. Specifically, PARPis are commonly used in BRCA-associated breast cancers patients, since unrepaired single-strand breaks are converted into double-strand breaks and BRCA-associated tumors cannot repair them by homologous recombination so that PARPi leads to tumor cell death, by a mechanism called "Synthetic Lethality". Unfortunately, not all patients respond to PARPi, and it is not currently possible to predict who will or will not respond. Here, we present a specific genomic marker, which reflects a single-nucleotide polymorphism of human PARP1 and correlates in vitro with response to PARPi, throughout all indications. In addition, we report that this SNP is associated with re-shaping mRNA, and mRNA levels, and influences the final protein structure to expose new binding sites while hiding others. The status of the SNP is therefore critical to patients' care, as it relates responses to PARPi to the PARP1-SNP carried.