title: The OncoPPi network of cancer-focused protein-protein interactions to inform biological insights and therapeutic strategies.
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.
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Zenggang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Andrei A
authors.initials: AA
authors.lastname: Ivanov
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.|Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China.|Department of Dermatology, Beijing Chao-yang Hospital, Capital Medical University, Beijing 100020, China.
authors.forename: Rina
authors.initials: R
authors.lastname: Su
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gonzalez-Pecchi
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Qi
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.|Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Songlin
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Webber
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75220, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McMillan
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Rusnak
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Cau
authors.initials: C
authors.lastname: Pham
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.|Department of Pathophysiology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Xiulei
authors.initials: X
authors.lastname: Mo
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Revennaugh
authors.affiliation: Department of Hematology &Medical Oncology, Emory University, Atlanta, Georgia 30322, USA.|Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Hematology &Medical Oncology, Emory University, Atlanta, Georgia 30322, USA.|Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Marcus
authors.affiliation: Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Sahar
authors.initials: S
authors.lastname: Harati
authors.affiliation: Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Johns
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75220, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: White
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.|Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.|Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Moreno
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.|Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.|Department of Biomedical Engineering, Georgia Institute of Technology/Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Lee A D
authors.initials: LA
authors.lastname: Cooper
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.|Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Hematology &Medical Oncology, Emory University, Atlanta, Georgia 30322, USA.|Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University, Atlanta, Georgia 30322, USA.|Department of Hematology &Medical Oncology, Emory University, Atlanta, Georgia 30322, USA.|Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D030562:Databases, Protein; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics*; D053263:Gene Regulatory Networks / Q000187:drug effects* / Q000235:genetics*; D016147:Genes, Tumor Suppressor / Q000187:drug effects; D016259:Genes, myc / Q000235:genetics; D023281:Genomics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D000091162:AMP-Activated Protein Kinase Kinases; D018797:Cell Cycle Proteins; D051358:Cyclin-Dependent Kinase 4; D011495:Histone-Lysine N-Methyltransferase; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C411762:RASSF1 protein, human; C432968:NSD3 protein, human; C109790:STK11 protein, human; C495900:CDK4 protein, human