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.
靶向疗法在配合精准诊断检测以识别可能对治疗产生应答的患者时，是有效的癌症治疗手段。YAP/TAZ-TEAD信号轴在多种癌症类型中被激活并发挥致病作用，目前TEAD抑制剂已在癌症患者中开展早期临床试验。然而，由于缺乏可靠的方法来鉴定大多数癌症类型中YAP/TAZ-TEAD激活的肿瘤，因此难以确定哪些肿瘤对TEAD抑制剂敏感。本研究通过结合RNA测序技术和生物信息学分析转移性黑色素瘤细胞，开发出YAP/TAZ基因特征谱。我们发现该特征谱中的基因在多种黑色素瘤细胞系中具有TEAD依赖性，且其表达水平与人类黑色素瘤中YAP/TAZ激活状态高度相关。通过DepMap依赖性数据分析，我们发现该YAP/TAZ特征谱能够预测黑色素瘤细胞对YAP/TAZ或TEAD的依赖性。重要的是，这种预测能力不仅限于黑色素瘤，当在代表多种不同癌症类型的1000多个癌细胞系中进行测试时，该特征谱同样具有预测效力。我们的研究结果表明，类似本研究开发的YAP/TAZ基因特征谱可作为预测肿瘤细胞对YAP/TAZ-TEAD依赖性的有效工具，从而为识别可能从TEAD抑制剂治疗中获益的患者提供潜在方法。
Identification of a Gene Signature That Predicts Dependence upon YAP/TAZ-TEAD
肿瘤(癌症)患者之家