Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment
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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
Franco J. Vizeacoumar, email: firstname.lastname@example.org
Andrew Freywald, email: email@example.com
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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