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Potential Strategy for Overcoming Resistance to BRAF Inhibitors in Melanoma

By: Joseph Fanelli
Posted: Wednesday, January 23, 2019

According to findings reported in EBioMedicine (published by The Lancet), the urokinase type plasminogen activator receptor (uPAR) may contribute to development of drug resistance in BRAF inhibitor therapy in patients treated for melanoma. High levels of uPAR seem to lower the sensitivity to vemurafenib in BRAF-mutant cells, whereas uPAR loss of function appeared to increase the susceptibility to vemurafenib and restore responsiveness in BRAF inhibitor–acquired resistant cells, authors concluded.

“Understanding the mechanisms of interaction between uPAR and different tyrosine kinase receptors offers the potential to reveal new opportunities for overcoming drug resistance and to design drug combinations that will lead to more potent, durable individualized treatment,” concluded Anna Laurenzana, PhD, of the University of Florence, Italy, and colleagues.

The researchers examined uPAR and EGFR levels by real time protein-coupled receptors and Western blot analysis. uPAR loss of function “was realized by knocking down uPAR by RNAi or by using the peptide m25.”

Results showed a direct association between uPAR and EGFR co-expression levels and vemurafenib responsiveness in V600E BRAF–mutated melanoma cells. Higher phosphorylated levels of ERK1/2 was associated with distance and simultaneous expression of both uPAR and EGFR protein levels in three of seven cell lines. Additionally, the authors “proved that uPAR knockdown in combination with vemurafenib inhibits melanoma cell proliferation to a greater extent than either treatment alone.”

Disclosure: The study authors’ disclosure information may be found at ebiomedicine.com.



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