Abstract 1740: CCR5/CCL5 axis inhibition reverses cisplatin-chemoresistance phenotye in gastric cancer cells

Abstract

Abstract Gastric cancer (GC) is an important public health problem worldwide. Advanced GC treatment is mainly based in chemotherapy with Cisplatin (CDDP). Unfortunately, the high recurrence rate of GC is predominantly attributable to chemoresistance. The CCR5/CCL5 axis, that participates in inflammatory process, has been associated with the development and progression of cancer. However, its role in GC chemoresistance has not been fully elucidated. The objective of this work was to elucidate the role of CCR5/CCL5 axis on GC chemoresistance cells. AGS R-CDDP was established through a method based on stepwise increasing drug doses and characterized by functional assays. RNA-Sequencing (RNA-seq) was performed on Illumina HiSeq 4000. A fold change >2 and P<0.05 were used as cut-off to choose the differentially expressed genes (DEGs). Gene Ontology (GO) and signaling pathways analysis were analyzed by PANTHER. CCL5 candidate gene was validated by qRT-PCR. Signaling pathways such as STAT3, MAPK and PI3K, associated with cytokines, proliferation and survival were evaluated by western blot assays. Cell viability of CCR5/CCL5 axis inhibition was evaluated in AGS R-CDDP exposed to Chemokine receptor antagonist (CRA) alone and in combination with CDDP. Characterization studies have effectively demonstrated that AGS R-CDDP is a reliable CDDP-resistant model. Bioinformatics analyses identified a total of 189 DEGs associated mainly to molecular functions (GO) involved in CDDP-resistance. The most enriched signaling pathway was the inflammation mediated by chemokine and cytokine which could be involved in the development of CDDP resistance in GC. CCL5 was upregulated in AGS R-CDDP cells. The main signaling pathways associated with CCR5/CCL5 axis were not activated in resistant GC cells compared parental GC cells.The cytotoxicity assays showed that CRA/CDDP combination re-sensitized AGS R-CDDP cells, decreasing cell viability. Our results indicate that CCR5/CCL5 axis induce chemoresistance and CRA/CDDP combination sensitize AGS R-CDDP cells revealing its potential as coadjuvant in GC therapy. Citation Format: Priscilla Brebi, Maria Elena Reyes, Carmen Gloria Ili, Yuselin Mora, Kurt Buchegger, Ismael Riquelme, Louise Zanella, Lorena Lobos-Gonzalez, Camila Burdiles, Barbara Mora-lagos. CCR5/CCL5 axis inhibition reverses cisplatin-chemoresistance phenotye in gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1740.