PDF(Pubmed)
Abstract：
Targeted therapies are effective cancer treatments when accompanied by accurate diagnostic tests that can help identify patients that will respond to those therapies. The YAP/TAZ-TEAD axis is activated and plays a causal role in several cancer types, and TEAD inhibitors are currently in early-phase clinical trials in cancer patients. However, a lack of a reliable way to identify tumors with YAP/TAZ-TEAD activation for most cancer types makes it difficult to determine which tumors will be susceptible to TEAD inhibitors. Here, we used a combination of RNA-seq and bioinformatic analysis of metastatic melanoma cells to develop a YAP/TAZ gene signature. We found that the genes in this signature are TEAD-dependent in several melanoma cell lines, and that their expression strongly correlates with YAP/TAZ activation in human melanomas. Using DepMap dependency data, we found that this YAP/TAZ signature was predictive of melanoma cell dependence upon YAP/TAZ or TEADs. Importantly, this was not limited to melanoma because this signature was also predictive when tested on a panel of over 1000 cancer cell lines representing numerous distinct cancer types. Our results suggest that YAP/TAZ gene signatures like ours may be effective tools to predict tumor cell dependence upon YAP/TAZ-TEAD, and thus potentially provide a means to identify patients likely to benefit from TEAD inhibitors.
摘要：
靶向疗法是有效的癌症治疗方法，伴随着准确的诊断测试，可以帮助识别对这些疗法有反应的患者。YAP/TAZ-TEAD轴被激活，并在几种癌症类型中起因果作用。和TEAD抑制剂目前正在癌症患者的早期临床试验中。然而,对于大多数癌症类型,由于缺乏鉴定具有YAP/TAZ-TEAD激活的肿瘤的可靠方法,因此难以确定哪些肿瘤对TEAD抑制剂易感.这里,我们使用RNA-seq和生物信息学分析的组合对转移性黑色素瘤细胞进行分析,以建立YAP/TAZ基因签名.我们发现该标记中的基因在几种黑色素瘤细胞系中是TEAD依赖性的，并且它们的表达与人黑色素瘤中YAP/TAZ的激活密切相关。使用DepMap依赖数据，我们发现YAP/TAZ特征可预测黑色素瘤细胞对YAP/TAZ或TEAD的依赖性.重要的是,这不仅限于黑色素瘤,因为当在代表许多不同癌症类型的超过1000个癌细胞系的小组中进行测试时,该特征也具有预测性.我们的结果表明，像我们这样的YAP/TAZ基因特征可能是预测肿瘤细胞对YAP/TAZ-TEAD依赖的有效工具。因此，有可能提供一种方法来鉴定可能受益于TEAD抑制剂的患者。
