RT Journal Article SR Electronic T1 Copy number aberrations drive kinase re-wiring leading to genetic vulnerabilities in cancer JF bioRxiv FD Cold Spring Harbor Laboratory SP 515932 DO 10.1101/515932 A1 Danish Memon A1 Michael B. Gill A1 Eva Papachristou A1 David Ochoa A1 Clive D’Santos A1 Martin L. Miller A1 Pedro Beltrao YR 2019 UL http://biorxiv.org/content/early/2019/01/09/515932.abstract AB 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.