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AACR 官方博客《Cancer Research Catalyst》发文：什么是合成致死性？

08月19日

来源：癌症研究UPDATE

以下内容原文发布于AACR官方博客《Cancer Research Catalyst》, 中文内容仅做参考，请点击文末“阅读原文”，阅览原文内容。

试想一下，您正开车行驶在回家的路上，但常走的那条路遇到了封路情况。幸运的是，另一条回家的路是畅通的，于是您改变了路线，轻松回家。

但如果两条路都被封了，没有路可以回家呢？

这正是“合成致死性”的背景理念，该理论也是研究人员用来治疗癌症的众多创新策略之一。

正常情况下，细胞会通过不同的修复途径修复DNA的常规损伤。然而，部分癌细胞内的一种名为BRCA的基因发生了突变，导致其中一条修复途径失活，从而封闭了这条“道路”。携带该突变的癌细胞仍然可以通过另一种迂回途径来修复DNA损伤，使细胞存活并继续生长。

而在几年前，研究人员发现，如果使用药物阻断“迂回”修复途径，癌细胞就无法修复DNA损伤。这使得本就不健康的细胞状态逐渐恶化，最终导致细胞死亡。

通过“封闭”这两条“道路”，这种药物就此终结了癌细胞的“旅程”。

了解更多内容，请阅读以下原文。

What Is Synthetic Lethality?

Imagine you’re driving home, and you come to a road closure on your normal route. Fortunately, another road that heads home is open, so you change routes and make it home easily.

But what if both roads were closed, and there was no way home?

This is the idea behind synthetic lethality, one of the many innovative strategies researchers are using to treat cancer.

Normally, cells fix routine damage to their DNA through different repair pathways. Some cancer cells, however, carry a mutation in a gene called BRCA that inactivates one of those repair pathways—essentially closing that “road.” Cancer cells with this mutation can still repair DNA damage through another repair pathway—a detour of sorts—allowing them to stay alive and keep growing.

Several years ago, researchers discovered that if they used a drug to block the “detour” repair pathway, then the cancer cells couldn’t repair the damage to their DNA. This caused the already unhealthy cells to become progressively unhealthier, which ultimately led to their death.

By “closing” both “roads,” the drug ended the cancer cells’ journey.

WHICH TREATMENTS USE SYNTHETIC LETHALITY?

Olaparib (Lynparza), the first drug to use this approach to treat cancer, was approved in 2014 to treat ovarian cancers that had a BRCA mutation. Olaparib works by inhibiting a DNA repair protein called PARP to shut off the “detour” repair pathway. Since the 2014 approval, olaparib and other PARP inhibitors have been approved to treat various BRCA-mutated cancers, either alone or in combination with other therapies.

Olaparib is approved for certain ovarian, breast, pancreatic, and prostate cancers.
Rucaparib (Rubraca) is approved for certain ovarian and prostate cancers.
Niraparib (Zejula) is approved for certain ovarian, fallopian tube, or peritoneal cancers.
Talazoparib (Talzenna) is approved for certain breast and prostate cancers.

Researchers continue to explore new synthetic lethality approaches to treat cancer—testing PARP inhibitors in different cancers, looking for additional drug targets in DNA repair pathways, and studying other cellular pathways that could drive synthetic lethality in cancers that carry other types of mutations.

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