Copy number aberrations drive kinase rewiring, leading to genetic vulnerabilities in cancer

• Published in: Cell reports (Cambridge) Vol. 35; no. 7; p. 109155
• Main Authors: Memon, Danish, Gill, Michael B., Papachristou, Evangelia K., Ochoa, David, D’Santos, Clive S., Miller, Martin L., Beltrao, Pedro
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-05-2021; Cell Press; Elsevier
• Subjects: cancer; copy number aberrations; DNA Copy Number Variations - genetics; genetic associations; Genomics - methods; Humans; kinase addiction; Neoplasms - genetics; phospho-regulation; precision medicine; Proteomics - methods; genetic associations; precision medicine; cancer; copy number aberrations; phospho-regulation; kinase addiction
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109155

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.
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•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.