Abstract 4751: Overcoming cisplatin resistance of esophageal squamous cell carcinoma by targeting RAC1-regulated Warburg effect

Abstract

Abstract Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with poor prognosis. Despite treatment advances, development of chemo-resistance remains a major challenge in treating ESCC patients. Ras-related C3 botulinum toxin substrate 1 (RAC1) is essential in regulating cancer progression. However, its role in chemo-resistance of ESCC and the underlying mechanisms are still unknown. In this study, we found that higher levels of RAC1 expression were associated with poorer disease-free survival (p=0.014) and overall survival (p=0.013) by immunohistochemistry in human ESCC samples (n=106). The over-expression of RAC1 was correlated with enhanced cell proliferation, migration, invasion and chemo-resistance in both KYSE150 and KYSE510 cells, while the knockdown of RAC1 produced the opposite results. The combination of RAC1 inhibitor EHop-016 with cisplatin significantly promoted cell viability reduction, cycle arrest at G2/M phase and apoptosis when compared with the single treatment. To examine the in vivo effects of RAC1 inhibition on chemo-resistance, we performed xenograft implantation studies in immunocompromised mice (n=10 per group). In the combination group, the tumor volume was significantly reduced to 21.4% (p<0.001) as compared to the single treatment groups (cisplatin: 62.7%, RAC1 inhibitor: 58.5%). Mechanistically, the RNA-Seq data indicated that the glycolytic pathway was significantly down-regulated in the EHop-016-treated group (p<0.001, Log2FC=1.86) and the combination group (p<0.001, Log2FC=1.76), as compared to the control group. Moreover, the qRT-PCR and western blot results confirmed that RAC1 inhibitor alone or the combination treatment suppressed Akt/FOXO signaling and resulted in inhibition of key enzymes such as PKM2, LDH-A, ALDOA and HK1 for the Warburg effect. Overall, our study suggests that inhibition of RAC1 overcomes cisplatin resistance in ESCC both in vitro and in vivo, and provides a novel mechanism of chemo-resistance in ESCC. Therefore, targeting RAC1 might be a promising and potent strategy for treating ESCC in clinical practice. Citation Format: Ruijie Zeng, Chunwen Zheng, Jinge Gu, Liu Peng, Haixia Zhang, Pan Feng, Yang Chen, Xiue Xu, Liyan Xu, Enmin Li. Overcoming cisplatin resistance of esophageal squamous cell carcinoma by targeting RAC1-regulated Warburg effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4751.