癌细胞中的基因改变会触发致癌转化，这一过程大多由激酶和转录因子 (TF) 活动的调节失调所介导。虽然成千上万个肿瘤的突变谱已被广泛研究，但蛋白活性的测量直到最近才得以技术上的限制。我们编制了1,110个肿瘤和77个细胞系的匹配基因组学和 (磷酸)蛋白质组测量的公共数据，用来估计218个激酶和292个TF的活性变化。激酶和TF活性的共调控反映了先前已知的调节关系，使我们能够解析癌症信号变化的遗传驱动因素。我们发现，功能丧失突变通常不会与下游靶标的失调相关联，表明经常存在补偿机制。最后，我们确定了在癌症亚型中差异最大的活性，并展示了这些活性如何与患者生存差异相关联。我们的结果为了解癌症蛋白质活性的调节失调及其对疾病严重程度的贡献提供了广泛的见解。© 2023 The Authors. 以 CC BY 4.0 许可条款发表。

Genetic alterations in cancer cells trigger oncogenic transformation, a process largely mediated by the dysregulation of kinase and transcription factor (TF) activities. While the mutational profiles of thousands of tumours have been extensively characterised, the measurements of protein activities have been technically limited until recently. We compiled public data of matched genomics and (phospho)proteomics measurements for 1,110 tumours and 77 cell lines that we used to estimate activity changes in 218 kinases and 292 TFs. Co-regulation of kinase and TF activities reflects previously known regulatory relationships and allows us to dissect genetic drivers of signalling changes in cancer. We find that loss-of-function mutations are not often associated with the dysregulation of downstream targets, suggesting frequent compensatory mechanisms. Finally, we identified the activities most differentially regulated in cancer subtypes and showed how these can be linked to differences in patient survival. Our results provide broad insights into the dysregulation of protein activities in cancer and their contribution to disease severity.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.