Research Papers:

Functional oncogene signatures guide rationally designed combination therapies to synergistically induce breast cancer cell death

Stephen T. Guest _, Zachary R. Kratche, Jonathan C. Irish, Robert C. Wilson, Ramsi Haddad, Joe W. Gray, Elizabeth Garrett-Mayer and Stephen P. Ethier

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Oncotarget. 2016; 7:36138-36153. https://doi.org/10.18632/oncotarget.9147

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Stephen T. Guest1, Zachary R. Kratche1, Jonathan C. Irish1, Robert C. Wilson1, Ramsi Haddad1, Joe W. Gray3,4, Elizabeth Garrett-Mayer2, Stephen P. Ethier1

1Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA

2Department of Public Health Science, Medical University of South Carolina, Charleston, South Carolina, USA

3Department of Biomedical Engineering, Oregon Health and Sciences University, Portland, Oregon, USA

4Knight Cancer Institute, Oregon Health and Sciences University, Portland, Oregon, USA

Correspondence to:

Stephen T. Guest, email: [email protected]

Keywords: breast cancer, functional genomics, BCL2L1, FGFR, AKT

Received: January 28, 2016     Accepted: April 10, 2016     Published: May 02, 2016


A critical first step in the personalized approach to cancer treatment is the identification of activated oncogenes that drive each tumor. The Identification of driver oncogenes on a patient-by-patient basis is complicated by the complexity of the cancer genome and the fact that a particular genetic alteration may serve as a driver event only in a subset of tumors that harbor it. In this study, we set out to identify the complete set of functional oncogenes in a small panel of breast cancer cell lines. The cell lines in this panel were chosen because they each contain a known receptor tyrosine kinase (RTK) oncogene. To identify additional drivers, we integrated functional genetic screens with copy number and mutation analysis, and cancer genome knowledge databases. The resulting functional oncogene signatures were able to predict responsiveness of cell lines to targeted inhibitors. However, as single agents, these drugs had little effect on clonogenic potential. By contrast, treatment with drug combinations that targeted multiple oncogenes in the signatures, even at very low doses, resulted in the induction of apoptosis and striking synergistic effects on clonogenicity. In particular, targeting a driver oncogene that mediates AKT phosphorylation in combination with targeting the anti-apoptotic BCL2L1 protein had profound effects on cell viability. Importantly, because the synergistic induction of cell death was achieved using low levels of each individual drug, it suggests that a therapeutic strategy based on this approach could avoid the toxicities that have been associated with the combined use of multiple-targeted agents.

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