title: Targeting synthetic lethality between the SRC kinase and the EPHB6 receptor may benefit cancer treatment.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.
authors.forename: James M
authors.initials: JM
authors.lastname: Paul
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada.
authors.forename: Behzad
authors.initials: B
authors.lastname: Toosi
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada.
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Vizeacoumar
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada.
authors.forename: Kalpana Kalyanasundaram
authors.initials: KK
authors.lastname: Bhanumathy
authors.affiliation: Department of Computer Science, University of Toronto, Toronto, ON, M5S 3G4, Canada.|The Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada.|Present address: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada.
authors.forename: Courtney
authors.initials: C
authors.lastname: Gerger
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada.|Faculty of Science, Damanhour University, Damanhour, 22516, Egypt.
authors.forename: Amr
authors.initials: A
authors.lastname: El Zawily
authors.affiliation: Cancer Research, Saskatchewan Cancer Agency, Saskatoon, SK, S7N 5E5, Canada.
authors.forename: Tanya
authors.initials: T
authors.lastname: Freywald
authors.affiliation: Cancer Research, Saskatchewan Cancer Agency, Saskatoon, SK, S7N 5E5, Canada.
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Anderson
authors.affiliation: Cell Signaling Laboratory, Neuroscience Cluster, University of Saskatchewan, Saskatoon, SK, S7N 5E5, Canada.
authors.forename: Darrell
authors.initials: D
authors.lastname: Mousseau
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada.
authors.forename: Rani
authors.initials: R
authors.lastname: Kanthan
authors.affiliation: Department of Computer Science, University of Toronto, Toronto, ON, M5S 3G4, Canada.|The Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada.
authors.forename: Zhaolei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada.|Cancer Research, Saskatchewan Cancer Agency, Saskatoon, SK, S7N 5E5, Canada.
authors.forename: Franco J
authors.initials: FJ
authors.lastname: Vizeacoumar
authors.affiliation: Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, S7N 0W8, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Freywald
mesh_terms: D000081:Acetamides / Q000737:chemistry; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000628:therapy*; D016923:Cell Death; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000737:chemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009025:Morpholines; D011725:Pyridines / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D036081:Receptors, Eph Family / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry; D000072020:Synthetic Lethal Mutations; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000081:Acetamides; D005456:Fluorescent Dyes; D007211:Indoles; D009025:Morpholines; D011725:Pyridines; D034741:RNA, Small Interfering; C416927:SU 6656; D013449:Sulfonamides; C000713668:tirbanibulin; C106797:EPHB6 protein, human; D036081:Receptors, Eph Family; D019061:src-Family Kinases
keywords: EPHB6; SRC kinase; breast cancer; genetic interaction; synthetic lethality