The OncoPPi network of cancer-focused protein-protein interactions to inform biological insights and therapeutic strategies

• Type of Material: Article
• Authors: Zenggang Li, Emory University; Andrey Ivanov, Emory University; Rina Su, Emory University; Valentina Gonzalez-Pecchi, Emory University; Qi Qi, Emory University; Songlin Liu, Emory University; Philip Webber, Emory University; Elizabeth McMillan, University of Texas Southwestern Medical Center; Lauren Rusnak, Emory University; Cau Pham, Emory University; Xiaoqian Chen, Emory University; Xiulei Mo, Emory University; Brian Revennaugh, Emory University; Wei Zhou, Emory University; Adam Marcus, Emory University; Sahar Harati, Emory University; Xiang Chen, Central South University; Margaret A. Johns, Emory University; Michael A. White, University of Texas Southwestern Medical Center; Carlos Moreno, Emory University; Lee Cooper, Emory University; Yuhong Du, Emory University; Fadlo Khuri, Emory University; Haian Fu, Emory University
• Language: English
• Date: 2017-02-16
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2017 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms14356
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 8
• Start Page: 14356
• End Page: 14356
• Grant/Funding Information: MAW and EAM were supported by R35CA197717 and U01CA176284.; This research was supported in part by NIH NCI U01CA168449 (HF), P01 CA116676 and 3P01 CA116676-05S1 (FRK), and a Georgia Cancer Coalition Award from Georgia Research Alliance (to HF, FRK), the Emory Chemical Biology Discovery Center, Winship Cancer Institute (NIH 5P30CA138292), and Emory University Research Committee grant (to A.I.).
• Keywords: Cancer genomics; High-throughput screening; Lung cancer; Biochemical networks
• Research Categories: Chemistry, Biochemistry; Biology, Genetics; Health Sciences, Oncology

Abstract

As genomics advances reveal the cancer gene landscape, a daunting task is to understand how these genes contribute to dysregulated oncogenic pathways. Integration of cancer genes into networks offers opportunities to reveal protein-protein interactions (PPIs) with functional and therapeutic significance. Here, we report the generation of a cancer-focused PPI network, termed OncoPPi, and identification of >260 cancer-associated PPIs not in other large-scale interactomes. PPI hubs reveal new regulatory mechanisms for cancer genes like MYC, STK11, RASSF1 and CDK4. As example, the NSD3 (WHSC1L1)-MYC interaction suggests a new mechanism for NSD3/BRD4 chromatin complex regulation of MYC-driven tumours. Association of undruggable tumour suppressors with drug targets informs therapeutic options. Based on OncoPPi-derived STK11-CDK4 connectivity, we observe enhanced sensitivity of STK11-silenced lung cancer cells to the FDA-approved CDK4 inhibitor palbociclib. OncoPPi is a focused PPI resource that links cancer genes into a signalling network for discovery of PPI targets and network-implicated tumour vulnerabilities for therapeutic interrogation.