Investigation of signalling pathways associated with the development of BRAF inhibitor resistance and treatment of melanoma
Boz Er, Asiye B.
Boz Er, Asiye B.
Publication Date
End of Embargo
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The University of Bradford theses are licenced under a Creative Commons Licence.
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Accepted for publication
Institution
University of Bradford
Department
Institute of Cancer Therapeutics. Faculty of Life Sciences
Awarded
2023
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Additional title
Investigation of the role of RGD-binding integrins and associated sig-nalling pathways in the development of BRAF inhibitor resistance and a new combination therapy approach for metastatic melanoma
Abstract
Metastatic melanoma is the most deadly type of skin cancers. It is the fifth most common cancer in UK. BRAF V600E mutation is observed in approximately 50% of melanomas and causes excessive stimulation of the MAPK signalling leading to proliferation, metastasis and invasion. In BRAF V600E positive mela-noma patients, BRAF is inhibited to prevent MAPK over activity. However, after a while, BRAF inhibition induces different mechanisms resulting in gaining re-sistance to the inhibitor. It is known that there is an increase in the expression of integrins during the development of BRAFi resistance.
To understand which RGD binding integrins and mechanisms are involved in BRAFi resistance in melanoma cells, in this study, BRAFV600E mutant vemu-rafenib resistant cell lines were generated and gene expression analysis (2-ΔΔCt) for 25 different target genes compared between parental and resistant cells in the presence and absence of the integrin ligand fibrinogen to determine alterations in active pathways and integrin levels linked to resistance.
It was found that increased integrin β3, integrin α5 and PAI-1 and p21 levels were associated with vemurafenib resistant BRAFV600E melanoma cells and the TGF-β pathway is the major regulator. Combination of cilengitide with vemurafenib, showed a highly synergistic effect and significantly blocked the in-vasive and colony initiating features and also decreased ITGB3, ITGA5, PAI-1, p21 levels of resistant cells.
Altogether these findings emphasize the potential druggable role of integ-rin β3, integrin α5, PAI-1, p21 and can be beneficial to overcome drug resistance or develop better approaches to block tumourigenic properties.
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Thesis
Qualification name
PhD