| الوصف: |
Protein-Protein Interaction (PPI) networks can be useful scaffolds for the integration of whole cell multi-omics datasets that can aid significantly in drug discovery research. This study aims to use domain-domain interaction (DDI) data to produce high resolution protein interaction networks with enhanced topological insights for head and neck squamous cell carcinoma as well as the more well studies, triple negative breast cancer (TNBC). An extensive literature review identified 65 driver genes for HNSCC and 19 genes for TNBC which collectively had 557 and 316 protein domains. Eventually, 343/557 and 191/316 domains had well-annotated somatic mutations reported in COSMIC. PPI networks were created using BioGrid and STRING data and the top two hubs in PPI networks were TP53 for HNSCC and EGFR for TNBC, while the top two hubs in DDI networks were PF12796 (NOTCH) and PF07714 (EGFR) for HNSCC and TNBC networks, respectively. The top nodes in the densest sub-clusters based on module analysis in PPI networks were ERBB4, MET and NOTCH1 for HNSCC, and FGFR1, AR, and EGFR for TNBC. For DDI networks, the top nodes in the densest subcluster for HNSCC were PF06816 (NOTCH1-3), while for TNBC PF07714 domains from FGFR1, ERBB2 and EGFR were the top nodes. Our preliminary results re-emphasize the significance of NOTCH, EGFR and TP53, and their domains, in cancer networks. Next, we attempted to decipher potential candidates for drug repurposing and were able to map 20 out of the 31 FDA approved cancer drugs against proteins within our HNSCC network. EGFR was revealed as a hub gene in both HNSCC and TNBC networks with most of the therapies designed against the PF07714 kinase domain of EGFR. PF07714 is also a common domain in ERBB4, EPHA2, MAP2K1 and MET, and was targeted by different drugs in other cancer types. Next, we attempt to undertake an in vitro drug screen of all candidates against HNSCC cell lines to validate our in silico findings. Citation Format: Maryam Shah, Arsalan Riaz, Faisal Khan. Higher-resolution protein interaction networks for precision medicine: A case for drug repurposing in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6338. |
