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Author Notes:

Correspondence and requests for materials should be addressed to F.R.K. (email: frkhuri@aub.edu.lb and fkhuri@emory.edu) or to H.F. (email: hfu@emory.edu).

Z.l., A.A.I., R.S., V.G.-P., Q.Q., P.W., E.M., S.L., L.R., C.P., X.C. and X.-L.M. conducted the experiments and contributed to data interpretation.

A.A.I., S.H., X.C., M.A.J., B.R., W.Z., A.M., M.A.W., C.M., L.A.D.C., Y.D., F.R.K. and H.F. participated in data analysis, discussion and manuscript preparation.

Z.L., A.A.I., R.S., C.M., L.A.D.C., Y.D., F.R.K. and H.F. designed the experiments and wrote the paper; and all were involved in manuscript editing.

We thank Dr Kun-Liang Guan for the YAP1 vector, Dr Matthew Meyerson for the ARAF vector, Dr Wei Xu for the SMARCA4 vector, RIKEN Brain Science Institute for the Venus plasmid, Edward Prochownik for MYC reporter plasmids, and Fu lab members for helpful comments and experimental assistance. The results published here are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.

The authors declare no competing financial interests.

Subjects:

Research Funding:

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.).

MAW and EAM were supported by R35CA197717 and U01CA176284.

Keywords:

  • Biochemical networks
  • Cancer genomics
  • High-throughput screening
  • Lung cancer

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

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Journal Title:

Nature Communications

Volume:

Volume 8

Publisher:

, Pages 14356-14356

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© 2017 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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