Abstract 879: The AVERON Notebook to discover druggable cancer dependencies through the mutant-directed protein-protein interactions

Abstract Cancer is a devastating disease that takes more than 10 million lives every year. The genomic alterations, such as mutations in cancer driver genes, can disrupt the essential networks of protein-protein interactions (PPIs), dysregulating major oncogenic pathways and inducing the transformation. While some mutations can disrupt existing PPIs, others can create neomorph PPIs (neoPPIs), which are unnatural for wild-type counterparts. Discovery of such mutant-created neoPPIs is vital for understanding the molecular mechanisms of mutant-driven tumorigenesis and developing new personalized clinical strategies in cancer. However, systematic experimental interrogation of the clinical significance and biological functions of neoPPIs is highly challenging. To address this critical challenge, we develop a novel computational platform called AVERON Notebook for identifying new Actionable Vulnerabilities Enabled by Rewired Oncogenic Networks. The AVERON employs specially designed algorithms and statistical techniques to i) Assess and compare the levels of neoPPIs in cancer patients; ii) Examine their impact on clinical outcomes; iii) Identify distinctive sets of signature genes and oncogenic pathways regulated by individual neomorph PPIs; and iv) Discover clinically significant neoPPI-regulated genes with available clinical compounds and approved drugs. Together, the AVERON Notebook provides a powerful tool for exploring the functional consequences of tumor-driving mutations mediated through the neoPPI networks and sheds new light on previously unexplored clinically actionable dependencies enabled by neomorph PPIs in cancer patients. The AVERON Notebook is freely available onGitHub: https://github.com/aivanovlab/averon_notebook and Code Ocean: https://doi.org/10.24433/CO.7986101.v1 Acknowledgments: This work was supported in part by NCI’s Informatics Technology for Cancer Research (ITCR) Program (R21CA274620, A.A.I.), Mary Kay Foundation Grant for Cancer Research (A.A.I), NCI Emory Lung Cancer SPORE (P50CA217691, H.F.), NCI P01CA257906 (H.F.), Career Enhancement Program (A.A.I., P50CA217691), Winship Cancer Institute (NIH 5P30CA138292). Citation Format: Hongyue (Nicole) Chen, Sean Yeung, Brian Revennaugh, Haian Fu, Andrey A. Ivanov. The AVERON Notebook to discover druggable cancer dependencies through the mutant-directed protein-protein interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 879.