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

View ORCID ProfileDanish Memon, Michael G Gill, Eva Papachristou, View ORCID ProfileDavid Ochoa, Clive D'Santos, View ORCID ProfileMartin L Miller, View ORCID ProfilePedro Beltrao
doi: https://doi.org/10.1101/515932
Danish Memon
EMBL-EBI;
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Michael G Gill
Cancer Research UK Cambridge Institute
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Eva Papachristou
Cancer Research UK Cambridge Institute
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David Ochoa
EMBL-EBI;
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Clive D'Santos
Cancer Research UK Cambridge Institute
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Martin L Miller
Cancer Research UK Cambridge Institute
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Pedro Beltrao
EMBL-EBI;
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  • ORCID record for Pedro Beltrao
  • For correspondence: pedrobeltrao@gmail.com
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Abstract

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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 09, 2019.
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Copy number aberrations drive kinase re-wiring leading to genetic vulnerabilities in cancer
Danish Memon, Michael G Gill, Eva Papachristou, David Ochoa, Clive D'Santos, Martin L Miller, Pedro Beltrao
bioRxiv 515932; doi: https://doi.org/10.1101/515932
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Copy number aberrations drive kinase re-wiring leading to genetic vulnerabilities in cancer
Danish Memon, Michael G Gill, Eva Papachristou, David Ochoa, Clive D'Santos, Martin L Miller, Pedro Beltrao
bioRxiv 515932; doi: https://doi.org/10.1101/515932

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