Bioinformatics Characterization and Pre-clinical Studies on the Therapeutic Potential of All-Trans-Retinoic Acid in the Personalized Treatment of Gastric Cancer

<b>Background:</b> Gastric cancer is a heterogeneous type of neoplastic disease, and it lacks appropriate therapeutic options. There is an urgent need for the development of innovative pharmacological strategies, particularly in consideration of the potential stratified/personalized treatment of this tumour. All-Trans Retinoic acid (ATRA) is one of the active metabolites of vitamin-A. This natural compound is the first example of a clinically approved cyto-differentiating agent used to treat acute promyelocytic leukaemia. ATRA may have significant therapeutic potential also in the context of solid tumours, including gastric-cancer. The present study provides pre-clinical evidence supporting the use of ATRA in the treatment of gastric-cancer using high-throughput approaches. <br><br> <b>Methods:</b> The anti-proliferative action of ATRA was evaluated in 27 gastric-cancer cell-lines through RNA-Sequencing experiments. The results were validated on tissue-slice cultures from 13 gastric-cancer patients exposed to ATRA by performing additional RNA-sequencing studies. These data and the gastric-cancer RNA-sequencing data of the TCGA/CCLE datasets were used to conduct multiple computational analyses. <br><br> <b>Results:</b> Profiling of the large panel of gastric-cancer cell-lines for their quantitative response to the anti-proliferative effects of ATRA indicates that approximately half of the cell-lines are characterized by sensitivity to the retinoid. The constitutive transcriptomic profiles of these cell-lines permitted the construction of a model consisting of 42 genes whose expression correlates with ATRA-sensitivity. The model predicts that 45% of the TCGA gastric-cancers are sensitive to ATRA. The previously observed results were also consistently obtained in the tissue-slice cultures. RNA-sequencing studies conducted on retinoid-treated gastric-cancer cell-lines provide insights into the gene-networks underlying ATRA anti-tumour activity. <br><br> <b>Conclusions: </b>ATRA is endowed with significant therapeutic potential in the stratified/personalized treatment of gastric-cancer. The data represent the foundation for the design of clinical trials focusing on the use of ATRA in the targeted treatment of this heterogeneous tumour. The gene-expression model will enable the development of a predictive tool for selecting ATRA-sensitive gastric-cancer patients.