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Cancer Res. 2016 Dec 1;76(23):6785-6794. Epub 2016 Oct 10.

Signal-Oriented Pathway Analyses Reveal a Signaling Complex as a Synthetic Lethal Target for p53 Mutations.

Lu S1,2, Cai C1,2, Yan G3,4,5, Zhou Z3,6, Wan Y3,6, Chen V1,2, Chen L1,2, Cooper GF1,2, Obeid LM7, Hannun YA7, Lee AV8,3,4,5, Lu X9,2.

Author information

1
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania.
2
Center for Causal Discovery, University of Pittsburgh, Pittsburgh, Pennsylvania.
3
University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
4
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
5
Magee-Womens Research Institute, Pittsburgh, Pennsylvania.
6
Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
7
Department of Medicine, the State University of New York at Stony Brook, Stony Brook, New York.
8
Center for Causal Discovery, University of Pittsburgh, Pittsburgh, Pennsylvania. xinghua@pitt.edu leeav@upmc.edu.
9
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania. xinghua@pitt.edu leeav@upmc.edu.

Abstract

Defining processes that are synthetic lethal with p53 mutations in cancer cells may reveal possible therapeutic strategies. In this study, we report the development of a signal-oriented computational framework for cancer pathway discovery in this context. We applied our bipartite graph-based functional module discovery algorithm to identify transcriptomic modules abnormally expressed in multiple tumors, such that the genes in a module were likely regulated by a common, perturbed signal. For each transcriptomic module, we applied our weighted k-path merge algorithm to search for a set of somatic genome alterations (SGA) that likely perturbed the signal, that is, the candidate members of the pathway that regulate the transcriptomic module. Computational evaluations indicated that our methods-identified pathways were perturbed by SGA. In particular, our analyses revealed that SGA affecting TP53, PTK2, YWHAZ, and MED1 perturbed a set of signals that promote cell proliferation, anchor-free colony formation, and epithelial-mesenchymal transition (EMT). These proteins formed a signaling complex that mediates these oncogenic processes in a coordinated fashion. Disruption of this signaling complex by knocking down PTK2, YWHAZ, or MED1 attenuated and reversed oncogenic phenotypes caused by mutant p53 in a synthetic lethal manner. This signal-oriented framework for searching pathways and therapeutic targets is applicable to all cancer types, thus potentially impacting precision medicine in cancer. Cancer Res; 76(23); 6785-94.

PMID:
27758891
PMCID:
PMC5165695
DOI:
10.1158/0008-5472.CAN-16-1740
[Indexed for MEDLINE]
Free PMC Article

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