European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK; Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
Cell Rep. 2021 May 18;35(7):109155. doi: 10.1016/j.celrep.2021.109155.
Somatic DNA copy number variations (CNVs) are prevalent in cancer and can drive cancer progression, albeit with often uncharacterized roles in altering cell signaling states. Here, we integrate genomic and proteomic data for 5,598 tumor samples to identify CNVs leading to aberrant signal transduction. The resulting associations recapitulate known kinase-substrate relationships, and further network analysis prioritizes likely causal genes. Of the 303 significant associations we identify from the pan-tumor analysis, 43% are replicated in cancer cell lines, including 44 robust gene-phosphosite associations identified across multiple tumor types. Several predicted regulators of hippo signaling are experimentally validated. Using RNAi, CRISPR, and drug screening data, we find evidence of kinase addiction in cancer cell lines, identifying inhibitors for targeting of kinase-dependent cell lines. We propose copy number status of genes as a useful predictor of differential impact of kinase inhibition, a strategy that may be of use in the future for anticancer therapies.
体细胞 DNA 拷贝数变异 (CNVs) 在癌症中很常见，并且可以促进癌症的进展，尽管它们在改变细胞信号状态方面的作用通常没有特征。在这里，我们整合了 5598 个肿瘤样本的基因组和蛋白质组数据，以鉴定导致异常信号转导的 CNVs。由此产生的关联再现了已知的激酶-底物关系，进一步的网络分析优先考虑可能的因果基因。在泛肿瘤分析中我们确定的 303 个显著关联中，有 43%在癌细胞系中得到复制，包括在多种肿瘤类型中发现的 44 个稳健的基因-磷酸化位点关联。几个预测的 hippo 信号调节因子已通过实验验证。使用 RNAi、CRISPR 和药物筛选数据，我们在癌细胞系中发现了激酶成瘾的证据，确定了针对激酶依赖细胞系的靶向抑制剂。我们提出基因的拷贝数状态作为激酶抑制的差异影响的有用预测因子，这一策略在未来的抗癌治疗中可能有用。
