Copy number aberrations drive kinase re-wiring leading to genetic vulnerabilities in cancer

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 integrated genomic and proteomic data for 5598 tumor samples to identify CNVs leading to aberrant signal transduction. The resulting associations recapitulated known kinase-substrate relationships and further network analysis prioritized likely driver genes. A total of 44 robust pan-cancer gene-phosphosite associations were replicated in cell line samples. Of these, ARHGEF17, a predicted regulator of hippo-signaling, was further studied through (phospho)proteomics analysis where ARHGEF17 knockdown cells showed dys-regulation of hippo- and p38 signaling as well as immune related pathways. 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 useful predictors of differential impact of kinase inhibition, a strategy that may be of use in the future for anticancer therapies.

• Publication year

  2019

• Venue

  bioRxiv

• Publication date

  2019-01-09

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1101/515932
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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