Copy number aberrations drive kinase rewiring, leading to genetic vulnerabilities in cancer
| Autor: | Evangelia K. Papachristou, Michael Gill, Martin L. Miller, Danish Memon, Pedro Beltrao, Clive D'Santos, David Ochoa |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Proteomics
0301 basic medicine Cell signaling DNA Copy Number Variations QH301-705.5 Somatic cell precision medicine kinase addiction Computational biology Biology Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine RNA interference Neoplasms medicine Humans CRISPR cancer Copy-number variation Biology (General) phospho-regulation copy number aberrations genetic associations Cancer Genomics medicine.disease 030104 developmental biology Hippo signaling Signal transduction 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, 35 (7) Cell Reports, Vol 35, Iss 7, Pp 109155-(2021) Cell Reports |
| DOI: | 10.3929/ethz-b-000531935 |
| Popis: | Summary 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. Graphical abstract Highlights • Alterations in copy number and in signaling pathways are robustly associated in cancer • Differences in essentiality of phosphoproteins show evidence of kinase addiction • Copy number markers of dysregulated signaling suggest treatment stratification options Memon et al. show that copy number alterations can be used as molecular fingerprints to predict the activity of signaling pathways in cancer. Kinase dependencies of cancer cells can be exploited for targeted anticancer therapy. |
| Databáze: | OpenAIRE |
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