Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma

Abstract

Gastric adenocarcinoma (GAC) is the most common histological type of gastric cancer, the fifth according to the frequency and the third among the deadliest cancers. GAC high mortality is due to a combination of factors, such as silent evolution, late clinical presentation, underlying genetic heterogeneity, and effective mechanisms of chemoresistance (MOCs) that make the available antitumor drugs scarcely useful. MOCs include reduced drug uptake (MOC-1a), enhanced drug efflux (MOC-1b), low proportion of active agents in tumor cells due to impaired pro-drug activation or active drug inactivation (MOC-2), changes in molecular targets sensitive to anticancer drugs (MOC-3), enhanced ability of cancer cells to repair drug-induced DNA damage (MOC-4), decreased function of pro-apoptotic factors versus up-regulation of anti-apoptotic genes (MOC-5), changes in tumor cell microenvironment altering the response to anticancer agents (MOC-6), and phenotypic transformations, including epithelial-mesenchymal transition (EMT) and the appearance of stemness characteristics (MOC-7). This review summarizes updated information regarding the molecular bases accounting for these mechanisms and their impact on the lack of clinical response to the pharmacological treatment currently used in GAC. This knowledge is required to identify novel biomarkers to predict treatment failure and druggable targets, and to develop sensitizing strategies to overcome drug refractoriness in GAC.

The Emerging Role of Liquid Biopsy in Gastric Cancer

“…Several resistance mechanisms against HER-2 inhibition have already been described [ 83 ]. One such mechanism is downregulation of the ERBB2 at a transcriptional level, leading to lower HER2 expression and failure of HER-2 inhibition strategies [ 84 , 85 ]. In vitro and in vivo models with gastric cancer cell lines show that the activation of several alternative pathways is an alternative mechanism for developing resistance to HER2 inhibition.…”

Long non-coding RNA HNF1A-AS1 induces 5-FU resistance of gastric cancer through miR-30b-5p/EIF5A2 pathway

“…EMT is a biological process in which epithelial cells lose their polarity and acquire mesenchymal morphology [34] . Previous studies have reported that EMT plays a critical role in chemoresistance in various cancers including GC [35] , [36] , [37] . Therefore, our current study sought to explore the relationship between EIF5A2 and EMT in 5-FU resistance of GC.…”

Copy number alterations and epithelial-mesenchymal transition genes in diffuse and intestinal gastric cancers in Mexican patients

“…Using this experimental strategy, it was possible to generate a karyogram and obtain molecular signatures for diffuse and intestinal GC, and their relationship with CNA-EMT genes independently of age, gender, % CC, H. pylori presence/absence, TNM, and treatment (naïve samples in our set). In addition, our genomic analysis was focused on the molecular profile of GC, particularly involving alterations of EMTgenes, given their role in cancer progression as epithelial cell transformation to mesenchymal cells is fundamental to metastasis (32) and chemoresistance (33,34). Our results coincide with those previously reported in the literature, which provides validity and robustness to our findings and allows us to report novel data or not yet explored potential diagnostic, prognostic, and treatment response markers.…”