Efecte de la glicosilació sobre l’activitat i la resposta a tractaments de l’EGFR

Abstract

The Epidermal Growth Factor Receptor (EGFR) is a glycoprotein that belongs to the family of tyrosine kinase receptors and that it is usually altered in tumor cells. It has been reported that its inhibition decreases tumor proliferation and thus, it is an attractive target for antitumor therapies. There are currently two main strategies of EGFR inhibition: monoclonal antibodies and tyrosine kinase inhibitors (TKI). Unfortunately, the appearance of resistance and other factors limit often the effectiveness of these treatments. In order to study how certain changes in EGFR can affect target therapies against this receptor, we must understand its conformational dynamics. EGFR activation requires the binding of two monomers that, induced by the presence of a ligand, allow then the interaction of the kinase domains and initiate the downstream signaling. However, the deregulation of this receptor may be modulated by several factors, such as the glycosylation of its ectodomine. Tumor progression has been related with an alteration of EGFR glycosylation and it has been observed that aberrant glycosylations may affect both the binding of the ligand and its activation. Accordingly, to study the overall effect of glycosylation on the response to EGFR directed treatments requires a more profound investigation. This is the objective of this Degree Final Project. Based on the existing bibliographic information, it is widely accepted that the site and type of glycosylation influence EGFR conformation and activity. In spite of the controversy in some studies, it seems that terminal fucosylation and sialylation decrease the activity of this receptor. In contrast, other glycosylations such as core fucosylation and Lewis epitopes, increase the activity of EGFR. Moreover, it seems that the alteration of glycosylation could have an effect on EGFR response to treatments. According to current information, EGFR glycosylation does not seem to alter the binding of antibodies to the extracellular domain. However, studies on another member of the EGFR family, HER2, show the opposite. The most relevant result obtained in this project is that extracellular glycosylation of EGFR indirectly affects intracellular sensitivity to TKI. Finally, the need to find alternative treatments to fight emerging resistance and the demand for higher treatment specificity opens an avenue for glycosylation itself as a potential novel target against cancer