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      Synthetic lethal interactions of EPHB6 in breast cancer cells

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      PAUL-THESIS-2016.pdf (10.69Mb)
      Date
      2017-01-05
      Author
      Paul, James 1986-
      Type
      Thesis
      Degree Level
      Masters
      Metadata
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      Abstract
      Sequencing of tumor genomes has shown that many loss-of-function alterations exist in cancer cells. Some of these alterations are a product of the cancerous progression of such cells, while others play a causative role. Unlike gain-of-function or overexpression alterations, these loss-of-function alterations are difficult to target directly, meaning that alternative approaches are necessary. In this case, such alterations can be specifically targeted through utilizing synthetic lethal interactions, whereby simultaneous inhibition of a particular interacting partner gene causes lethality in the context of a previously inactivated gene. Such a loss-of-function alteration occurs in the case of the EPHB6 receptor tyrosine kinase, which is downregulated in multiple cancer types. This downregulation of EPHB6, along with its inherent anti-malignant properties, make it a logical target for the synthetic lethal approach. In my thesis, I describe the use of a large-scale genome-wide screen of EPHB6 in triple-negative beast caner cells to determine corresponding synthetic lethal genes, which may be therapeutically targeted. The screen revealed the SRC kinase as a synthetic lethal partner of EPHB6, whereby targeting of SRC in EPHB6-deficient cells results in lethality. In addition, small molecule SRC inhibitors, such as KX2-391, were used to improve elimination of EPHB6-deficient triple-negative breast cancer cells in both monolayer culture, as well as in xenograft tumor models. This work reveals EPHB6 to be a biomarker for the use of SRC inhibitors in triple negative breast cancer, and it contributes to larger synthetic lethal interaction maps of cancer as a whole.
      Degree
      Master of Science (M.Sc.)
      Department
      Biochemistry
      Program
      Biochemistry
      Supervisor
      Vizeacoumar, Franco; Freywald, Andrew
      Committee
      Lee, Jeremy; Lukong, Erique; Chelico, Linda
      Copyright Date
      December 2016
      URI
      http://hdl.handle.net/10388/7663
      Subject
      breast cancer
      genetic interaction
      synthetic lethality
      EPHB6
      SRC kinase
      KX2-391
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