Copy number aberrations drive kinase rewiring, 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 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.

Automated summary

The study integrated genomic and proteomic data from thousands of tumor samples to identify CNVs that play a key role in cancer by altering cell signaling states. Known kinase-substrate relationships were recapitulated, and potential causal genes were prioritized through network analysis. The research also showed evidence of kinase addiction in cancer cell lines and proposed the copy number status of genes as a useful predictor for impacting kinase inhibition in anticancer therapies.