Author:
Li Zenggang,Ivanov Andrei A.,Su Rina,Gonzalez-Pecchi Valentina,Qi Qi,Liu Songlin,Webber Philip,McMillan Elizabeth,Rusnak Lauren,Pham Cau,Chen Xiaoqian,Mo Xiulei,Revennaugh Brian,Zhou Wei,Marcus Adam,Harati Sahar,Chen Xiang,Johns Margaret A.,White Michael A.,Moreno Carlos S.,Cooper Lee A. D.,Du Yuhong,Khuri Fadlo R.,Fu Haian
Abstract
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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Cited by
153 articles.
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