Triple-negative breast cancer (TNBC) is an aggressive cancer subtype that displays poor prognosis due to a lack of targeted therapies and an early pattern of spread. Recent evidence also points to a correlation between cancer “stem-like” cells (CSCs) and the inherently aggressive traits of TNBC. As such, targeting signalling pathways which support metastasis and CSC populations may represent an important therapeutic strategy to treat these tumours and improve current patient outcomes. The non-receptor tyrosine kinase FAK (focal adhesion kinase) is known to influence cancer development and progression, with its upregulation common in several cancer types. Indeed, FAK can regulate various cellular processes associated with disease progression including, cell survival, migration and stem-like behaviours. Therefore, we explored the influence of FAK in TNBC cells and the potential benefit of its targeting in this subtype. Whilst assessment of FAK expression and activity across a panel of breast cancer cell lines representing the major clinical subtypes revealed that FAK was not significantly augmented in MDA-MB-231 cells (model of TNBC) versus other models, MDA-MB-231 cells displayed a FAK-dependent migratory and invasive behaviour involving FAK-mediated activation of Akt and STAT3. These observations also extended to cell proliferation, with pharmacological or genetic FAK inhibition leading to perturbed cell cycle progression. Whilst FAK did not contribute to the maintenance of a CSC subpopulation, FAK was necessary for their anoikis resistance and mammosphere self-renewal, the latter regulated by FAK-dependent modulation of β-catenin through GSK3β and interaction between the FAK/Wnt signalling pathways. Using computational modelling, several novel FAK inhibitors that targeted FAK kinase-independent scaffolding function were developed and screened to assess in vitro efficacy in TNBC cells. Of all 45 compounds, ‘compound 9’ showed significantly improved ability to reduce cell proliferation and migration versus the lead compound, chloropyramine. As expected, this agent had little effect of FAK phosphorylation but appeared to reduce focal-adhesion targeting and subcellular distribution of FAK and significantly inhibited cell migration and growth. Our in vitro data support a case for FAK as a promising therapeutic target in TNBC with an ability to suppress both tumorigenic events and those associated with metastasis. Targeting FAK scaffolding function may represent a novel approach to developing FAK inhibitors that can circumvent resistance traditionally associated with kinase inhibitors.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:738379 |
| Date | January 2017 |
| Creators | Jones, Samuel Rhys |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/110068/ |
Page generated in 0.0015 seconds