Abstract 4402: MiR-195 potentiates the efficacy of microtubule-targeting agents in non-small cell lung cancer

Abstract

Abstract Introduction: microRNAs (miRNAs) are a family of small noncoding RNAs (18-24 nt) that post-transcriptionally repress gene expression by direct binding to the 3' untranslated regions (UTRs) of their targets. By targeting cancer-related genes, miRNAs have been shown not only to regulate cancer growth/progression, but also to modulate the response of cancer cells to chemotherapy. Such miRNAs are potential candidates for therapeutic intervention. Aiming to identify functional miRNAs in non-small cell lung cancer (NSCLC), we performed a high-throughput screen and found that miR-195 inhibits the growth of NSCLC cells and sensitizes them to microtubule-targeting agents (MTAs), a family of chemotherapeutic drugs widely used for NSCLC treatment. The function and mechanism of miR-195 in NSCLC were demonstrated both in vitro and in vivo. Results: We demonstrated that miR-195 synergizes with both a traditional MTA (paclitaxel) and a recently discovered one (eribulin) to repress the growth of NSCLC cells. Overexpression of miR-195 sensitizes NSCLC cells to paclitaxel and eribulin, while knockout of miR-195 confers resistance to paclitaxel and eribulin. Importantly, lung tumors with miR-195 overexpression are more sensitive to eribulin treatment than control tumors. Induced expression of miR-195 in lung tumors potentiates the efficacy of eribulin to repress tumor growth. Additionally, we showed that miR-195 directly targets CHEK1 to regulate the response of NSCLC cells to paclitaxel and eribulin. The direct and specific binding of miR-195 to the 3'UTR of CHEK1 was confirmed by luciferase reporter assay. Repression of CHEK1 using siRNAs and chemical inhibitor synergizes with paclitaxel and eribulin to repress the growth of NSCLC cells. Overexpression of CHEK1 contributes to the resistance to paclitaxel and eribulin in NSCLC cells. Analysis of TCGA data shows that CHEK1 is significantly upregulated in lung tumors compared to adjacent normal tissues and that its upregulation is associated with worse recurrence-free and overall survival. Conclusions: We report the identification of miR-195 as a sensitizer to microtubule-targeting agents in NSCLC, mediated by its repression of CHEK1. Mouse xenografts with induced or constitutive overexpression of miR-195 show that tumors with high miR-195 expression are more sensitive to drug treatment and that induction of miR-195 potentiates the efficacy of eribulin in repressing tumor growth. These results highlight the possible application of miR-195 expression as a biomarker to predict patient response to MTAs and the potential for delivery of miR-195 mimic as an adjuvant to chemotherapy. Citation Format: Xiaojie Yu, Yiqiang Zhang, Xiuye Ma, Alexander Pertsemlidis. MiR-195 potentiates the efficacy of microtubule-targeting agents in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4402.