Evaluation of epithelial-mesenchymal transition protein expression as a new perspective in biomarkers for determining prognosis, response and resistance to targeted therapy in non-small cell lung carcinomas

Abstract

Recent studies have identified that the EGFR T790M mutation is responsible for acquired resistance to EGFR inhibitors in up to 50% of cases and that NSCLC strains that display wild-type EGFR exhibit sensitivity to EGFR inhibitors dependent on the degree to which they have been subjected to EMT. In contrast, EGFR inhibitor-resistant NSCLC strains with mesenchymal phenotype showed decreased E-cadherin expression and increased vimentin expression, suggesting that EMT may be a determinant of insensitivity to EGFR inhibition in lung cancer. XIE et al demonstrated that the NOTCH-1 gene is involved in the acquisition of resistance, by tumor cells, to treatment with drugs that inhibit epidermal growth factor receptor tyrosine kinase (EGFR-TKI) in NSCLC. Animal experiments demonstrate tumor regression related to a decrease in proliferative activity and an increase in apoptotic activity, in response to the inhibition of NOTCH-1 through the activity of its inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl] -(S)-phenylglycine t-butyl ester (DAPT). Zhang et al demonstrated that the mechanism of action of TGF-², through EMT, can facilitate the invasion and metastasis of lung adenocarcinoma through the EMT event by decreasing the gene expression of epithelial markers, such as E-cadherin, and increasing gene expression of mesenchymal markers, such as fibronectin and vimentin. Evaluating the participation of other molecules involved in EMT, Merikallio et al found that there was a greater expression of Snail in small cell carcinomas compared to squamous cell carcinomas and adenocarcinomas, with an important role in tumor invasion and reduced survival. Our group evaluated the gene expression related to EMT in lung carcinomas (FAPESP Project 2013-14277-4), so we were able to identify 24 genes that are overexpressed in lung carcinomas. However, it is necessary to test and evaluate the protein expression found in the tumor tissue by immunohistochemistry, since the analyzed genes are directly related to tumor invasion and metastasis, and may emerge as possible predictive and/or diagnostic biomarkers for the different histological types in lung cancer. It is worth mentioning that the study of biomarkers can open new frontiers for personalized therapy in lung cancer.