AVERON notebook to discover actionable cancer vulnerabilities enabled by neomorph protein-protein interactions

Genomic alterations, such as missense mutations, often lead to the activation of oncogenic pathways and cell transformation by rewiring protein-protein interaction (PPI) networks. Understanding how mutant-directed neomorph PPIs (neoPPIs) drive cancer is vital to developing new personalized clinical...

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Bibliographic Details
Published iniScience Vol. 27; no. 6; p. 110035
Main Authors Chen, Hongyue, Revennaugh, Brian, Fu, Haian, Ivanov, Andrey A.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 21.06.2024
Elsevier
Subjects
Biochemistry
Bioinformatics
Biological sciences
Natural sciences
Biological sciences
Biochemistry
Natural sciences
Bioinformatics
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Summary:Genomic alterations, such as missense mutations, often lead to the activation of oncogenic pathways and cell transformation by rewiring protein-protein interaction (PPI) networks. Understanding how mutant-directed neomorph PPIs (neoPPIs) drive cancer is vital to developing new personalized clinical strategies. However, the experimental interrogation of neoPPI functions in patients with cancer is highly challenging. To address this challenge, we developed a computational platform, termed AVERON for discovering actionable vulnerabilities enabled by rewired oncogenic networks. AVERON enables rapid systematic profiling of the clinical significance of neomorph PPIs across different cancer types, informing molecular mechanisms of neoPPI-driven tumorigenesis, and revealing therapeutically actionable neoPPI-regulated genes. We demonstrated the application of the AVERON platform by evaluating the biological functions and clinical significance of 130 neomorph interactions, experimentally determined for oncogenic BRAFV600E. The AVERON application to broad sets of mutant-directed PPIs may inform new testable biological models and clinical strategies in cancer. [Display omitted] •AVERON evaluates the biological functions and clinical significance of neomorph PPIs•Users can estimate and compare neoPPI levels across different cancer patient cohorts•AVERON uncovers neoPPI-regulated genes and maps them on defined pathways•AVERON identifies druggable clinically significant neoPPI-regulated genes Natural sciences; Biological sciences; Biochemistry; Bioinformatics
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ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2024.110035