Understanding the mechanisms underpinning therapeutic vulnerability of SWI/SNF deficient cancers

SWI/SNF染色质重塑复合体调控基因表达、DNA修复、复制应激反应和染色体分离。SWI/SNF基因在数量惊人的癌症中发生突变，这提供了治疗机会。通过识别合成致死关系，或在SWI/SNF缺陷细胞中生存所需的基因，我们可以选择性地针对癌症。针对几种已知的合成致死关系的抑制剂正在临床使用。然而，反应是多种多样的，目前还不清楚为什么一些SWI/SNF缺陷细胞容易受到攻击，而另一些细胞则不是。在这个项目中，我们将机械地探索这些漏洞，以了解在哪些情况下抑制剂最有效。

SWI/SNF chromatin remodelling complexes regulate gene expression, DNA repair, replication stress responses and chromosome segregation. SWI/SNF genes are mutated in a striking number of cancers, which provides therapeutic opportunities. By identifying synthetic lethal relationships, or genes required for viability in SWI/SNF deficient cells, we can selectively target the cancer. Inhibitors targeting several known synthetic lethal relationships are in clinical use. However, responses are variable, and it is not clear why some SWI/SNF deficient cells are vulnerable, yet others are not. In this project, we will mechanistically explore these vulnerabilities to understand the contexts in which inhibitors are most effective.