Research Papers:

Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment

James M. Paul, Behzad Toosi, Frederick S. Vizeacoumar, Kalpana Kalyanasundaram Bhanumathy, Yue Li, Courtney Gerger, Amr El Zawily, Tanya Freywald, Deborah H. Anderson, Darrell Mousseau, Rani Kanthan, Zhaolei Zhang, Franco J. Vizeacoumar and Andrew Freywald _

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Oncotarget. 2016; 7:50027-50042. https://doi.org/10.18632/oncotarget.10569

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James M. Paul1,*, Behzad Toosi2,*, Frederick S. Vizeacoumar2,*, Kalpana Kalyanasundaram Bhanumathy2, Yue Li3,4,5, Courtney Gerger2, Amr El Zawily2,6, Tanya Freywald7, Deborah H. Anderson7, Darrell Mousseau8, Rani Kanthan2, Zhaolei Zhang3,4, Franco J. Vizeacoumar2,7, Andrew Freywald2

1Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada

2Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada

3Department of Computer Science, University of Toronto, Toronto, ON, M5S 3G4, Canada

4The Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada

5Present address: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

6Faculty of Science, Damanhour University, Damanhour, 22516, Egypt

7Cancer Research, Saskatchewan Cancer Agency, Saskatoon, SK, S7N 5E5, Canada

8Cell Signaling Laboratory, Neuroscience Cluster, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada

*These authors contributed equally to this work

Correspondence to:

Franco J. Vizeacoumar, email: franco.vizeacoumar@usask.ca

Andrew Freywald, email: andrew.freywald@usask.ca

Keywords: breast cancer, genetic interaction, synthetic lethality, EPHB6, SRC kinase

Received: April 22, 2016     Accepted: June 17, 2016     Published: July 13, 2016


Application of tumor genome sequencing has identified numerous loss-of-function alterations in cancer cells. While these alterations are difficult to target using direct interventions, they may be attacked with the help of the synthetic lethality (SL) approach. In this approach, inhibition of one gene causes lethality only when another gene is also completely or partially inactivated. The EPHB6 receptor tyrosine kinase has been shown to have anti-malignant properties and to be downregulated in multiple cancers, which makes it a very attractive target for SL applications. In our work, we used a genome-wide SL screen combined with expression and interaction network analyses, and identified the SRC kinase as a SL partner of EPHB6 in triple-negative breast cancer (TNBC) cells. Our experiments also reveal that this SL interaction can be targeted by small molecule SRC inhibitors, SU6656 and KX2-391, and can be used to improve elimination of human TNBC tumors in a xenograft model. Our observations are of potential practical importance, since TNBC is an aggressive heterogeneous malignancy with a very high rate of patient mortality due to the lack of targeted therapies, and our work indicates that FDA-approved SRC inhibitors may potentially be used in a personalized manner for treating patients with EPHB6-deficient TNBC. Our findings are also of a general interest, as EPHB6 is downregulated in multiple malignancies and our data serve as a proof of principle that EPHB6 deficiency may be targeted by small molecule inhibitors in the SL approach.

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