Abstract
Abstract Gastric cancer is a deadly disease with a low 5-year survival rate of 32%. This disease is characterized by high rates of chemo resistance and late initial detection. We have previously reported that inhibition of nuclear exporter protein Exportin 1 (XPO1/CRM1) with the small molecule inhibitor selinexor (KPT-330) is a viable therapeutic approach in gastric cancer. Inhibition of XPO1 blocks proliferation and suppresses tumor growth through nuclear retention of tumor suppressor proteins such as TP53. Besides nuclear retention, we also demonstrated that XPO1 inhibition leads to a perturbation of cancer specific microRNAs including microRNA-7974 downregulation (miR-7974) and microRNA-129-1-3p upregulation (miR-129-1-3p) within a small RNA sequencing study. In this study we evaluated the role of these microRNAs in gastric cancer perpetuation in respect to their naive functions in five distinct subtypes of gastric cancer. Our results show over-expression of miR-7974 and loss of miR-129-1-3p promotes gastric cancer growth and progression, based on specific subtype of disease. We have further found that the differential expression of these microRNAs leads to gastric cancer cellular changes including cell cycle alterations, upregulation of autophagy processes, chemoresistance and alterations in the cellular framework leading to more invasive phenotypes. Validation with normal gastric epithelial cells revealed these microRNAs are relevant as they are perturbed in gastric cancer as well as the proteins in which they modulate. Finally, we have validated treatment of gastric cancer cells with the XPO1 inhibitor selinexor altered the expression of miR-7974 and miR-129-1-3p differently, based on subtype, as we have previously observed in small RNA sequencing screen, leading to a reversal of the pro-cancerous phenotypes previously observed. In vivo investigation is currently ongoing to identify whether we can capture either miR-7974 or miR-129-1-3p within the serum as further evidence of microRNA perturbation as a predictive biomarker for selinexor efficacy. Citation Format: Rachel E. Sexton, Amro Aboukameel, Yiwei Li, Husain Y. Khan, Md Hafiz Uddin, Trishyan Kashyap, Yosef Landesman, Anteneh Tesfaye, Asfar S. Azmi. Utilizing small noncoding RNAs as biomarkers for selinexor treatment in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5832.
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