Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.665878
Title: Focal Adhesion Kinase (FAK) as a novel therapeutic target in HER2+ breast cancer
Author: Lazaro, Glorianne
ISNI:       0000 0004 5351 6449
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2015
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Abstract:
Focal Adhesion Kinase (FAK) is an intracellular kinase known to mediate integrin signalling following cell adhesion to the extracellular matrix. It is now emerging as a promising therapeutic target in many tumour types due to its overexpression in tumour cells and is associated with various cellular processes involved in cancer progression. Given that existing literature demonstrating that FAK plays a key role in the transduction of HER2 signalling in HER2+ cells and that the levels of FAK expression strongly correlated with HER2 overexpression in clinical samples, we explored the potential for improvement of current therapies for HER2+ breast cancer by combination treatment strategies with the small molecule FAK inhibitor, PF878. FAK activity was assessed in a panel of cell lines reflecting HER2- (MCF7, T47D) and HER2+ (BT474, MDA-361, SKBr3) disease by Western blotting. FAK activity was relatively increased in HER2+ versus HER2- cell lines with HER2+ cells demonstrating greatest sensitivity to PF878 with respect to suppression of FAK phosphorylation at Y397. The effects of PF878 on cell proliferation as a monotherapy and in combination with Herceptin were assessed using MTT and direct coulter cell counting and by Ki67 immuno-staining. Whilst PF878 did not affect the proliferation as a monotherapy, treatment of HER2+ cells with PF878 and Herceptin combined resulted in synergistic inhibitory action on cell proliferation with an associated suppression in AKT pathway activity. This combination treatment strategy produced the greatest effects in MDA-361 cells which were intrinsically insensitive to Herceptin-monotherapy. Inhibition of FAK activity also suppressed HER2+ cell migration in response to the (1) exogenous ligand Heregulin and (2) conditioned-media derived from fibroblasts (FCM), as assessed in Boyden Chamber migration assays. In this latter context, our data suggests that FAK may act through a STAT3-dependent mechanism to regulate fibroblast-stimulated migratory and invasive responses. Collectively, these data support a role for FAK in HER2+ breast cancer where its targeting has the potential to improve Herceptin response as well as suppress stromal-induced signalling that can contribute to disease progression and spread.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.665878  DOI: Not available
Keywords: Q Science (General)
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