TARGETING EPHB6 SYNTHETIC LETHALITY IN BREAST CANCER
Date
2019-06-07
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0000-0002-0648-0119
Type
Thesis
Degree Level
Masters
Abstract
Traditionally, cancer treatments focus on proteins impacted by either an increase in expression or a gain-of-function mutation. Loss-of-function mutations or especially down-regulation usually cannot be targeted directly through stabilization or activation, so alternative approaches are needed to target these changes in cancer cells. One approach is based on the synthetic lethality concept, where lethality occurs only when inhibition of a gene partner to the loss-of-function alteration is inhibited. EphB6, a kinase-dead member of the Eph receptor tyrosine kinase family, has anti-malignant properties and is often down-regulated in breast cancer, making it a strong candidate for the synthetic lethality approach. To support the development of EphB6-based therapies, our lab previously completed a genome-wide shRNA screen in an effort to find novel EphB6 interactions, searching specifically for molecules synthetically lethal with EphB6 that also had FDA-approved inhibitors. One of the identified hits, the Src kinase, was successfully validated with and FDA-approved Src inhibitor, KX2-391, in triple-negative breast cancer models representing the most aggressive breast cancer subtype. Met was another promising target identified, but it was not properly validated. This thesis describes the further assessment of the EphB6-Src and EphB6-Met synthetic lethal interactions in various breast cancer subtypes. Also reported here is the screening of the library of over 1800 FDA-approved compounds that allowed us to identify a new drug (the INHIBITOR) synthetic lethal with EphB6 that selectively eliminates EphB6-deficient TNBC cells. The results laid out in this thesis strongly suggest that synthetic lethal interactions of EphB6 discovered in TNBC appear to be restricted to this breast subtype, and also indicate that using small-molecule Met inhibitors, especially ARQ-197, or the newly identified INHIBITOR could represent valuable options for treating TNBC patients with low EphB6 expression in tumor cells.
Description
Keywords
breast cancer, ephb6
Citation
Degree
Master of Science (M.Sc.)
Department
Biochemistry
Program
Biochemistry