癌症靶向治疗的范式主要集中在抑制癌症的关键途径。相反，信号通路的条件激活作为选择性癌症脆弱性的新来源尚未得到深入表征。在这项研究中，我们试图系统地识别特定环境下基因激活引起的癌症致死率。为此，我们开发了一种在约 500 个条形码癌细胞系中同时进行功能获得性遗传扰动的方法。使用这种方法，我们在激活十个关键通路节点时查询了泛癌脆弱性情况，揭示了与特定生物标志物相关的 MAPK 和 PI3K 通路的选择性激活依赖性。值得注意的是，我们在 APC 突变结直肠癌亚群中发现了新的通路过度激活依赖性，其中通过 APC 敲低或直接 β-连环蛋白过度表达进一步激活 WNT 通路，在异种移植和患者来源的类器官模型中产生强大的抗肿瘤作用。总之，这项研究揭示了癌症中一类新的条件基因激活依赖性。© 2023。作者获得 Springer Nature America, Inc. 的独家许可。

The paradigm of cancer-targeted therapies has focused largely on inhibition of critical pathways in cancer. Conversely, conditional activation of signaling pathways as a new source of selective cancer vulnerabilities has not been deeply characterized. In this study, we sought to systematically identify context-specific gene-activation-induced lethalities in cancer. To this end, we developed a method for gain-of-function genetic perturbations simultaneously across ~500 barcoded cancer cell lines. Using this approach, we queried the pan-cancer vulnerability landscape upon activating ten key pathway nodes, revealing selective activation dependencies of MAPK and PI3K pathways associated with specific biomarkers. Notably, we discovered new pathway hyperactivation dependencies in subsets of APC-mutant colorectal cancers where further activation of the WNT pathway by APC knockdown or direct β-catenin overexpression led to robust antitumor effects in xenograft and patient-derived organoid models. Together, this study reveals a new class of conditional gene-activation dependencies in cancer.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.