Synthetic lethal interactions of EPHB6 in breast cancer cells
Date
2017-01-05
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
Type
Thesis
Degree Level
Masters
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.
Description
Keywords
breast cancer, genetic interaction, synthetic lethality, EPHB6, SRC kinase, KX2-391
Citation
Degree
Master of Science (M.Sc.)
Department
Biochemistry
Program
Biochemistry