Abstract 420: Dicer-dependent of ERK activation promotes the acquired oxaliplatin resistance in colorectal cancer

Abstract

Abstract Introduction: Chemoresistance is one of the major challenges for cancer therapy. Oxaliplatin is the first-line therapy for most cancers, including colorectal cancer (CRC). However, the underlying mechanisms of oxaliplatin resistance remain elusive. Previous reports indicated that microRNAs might regulate the development of CRC. Dicer, an endonuclease involved in miRNA biogenesis, may play a critical role in oxaliplatin resistance. Here, we investigated the mechanism of Dicer-mediated oxaliplatin resistance in CRC. Materials and Methods: Oxaliplatin-resistant CRC cells were established. Colony formation, migration, invasion, and sphere formation assays were performed to characterize the properties of oxaliplatin-resistant CRC cells. cDNA microarray and NGS were used to identify the altered expression of mRNAs and miRNAs in oxaliplatin-resistant cells. RT-qPCR determined gene expression. A connectivity map (CMAP) database was used to find the potential drugs which can reduce cell viability in oxaliplatin-resistant cells. CCK-8 assay was used to measure the anti-tumor effect of those potential drugs in oxaliplatin-resistant CRC cells. PANTHER was used to find the potential pathways that may involve drug resistance in CRC. Both reporter assay and western blot analyzed the activation of the Wnt/β-catenin and MAPK signaling pathways. Results: Dicer is overexpressed in oxaliplatin-resistant CRC cells and CRC recurrent patients. Overexpressed Dicer attenuated the cytotoxicity of oxaliplatin and promoted the cell migration, invasion, and stem cell properties of the oxaliplatin-resistant cells. Knocked-down of Dicer restored the chemosensitivity and decreased all of those abilities in oxaliplatin-resistant CRC cells. The expression of several potential mRNAs and microRNAs was changed in drug-resistant cells and chemo-resistant CRC patients' plasma. MAPK and Wnt/β-catenin pathways are hyper-activated in oxaliplatin-resistant CRC cells. PRI-724, a Wnt/β-catenin pathway inhibitor, can increase the cell apoptosis of oxaliplatin-resistant CRC cells. Trametinib, the MEK inhibitor, can induce cell apoptosis in oxaliplatin-resistant CRC cells and present an anti-tumor effect in oxaliplatin-resistant CRC cell-derived xenograft tumors. Knocked-down expression of Dicer did not affect the Wnt/β-catenin pathway but attenuated the ERK activation. A combination of oxaliplatin and trametinib can synergistically inhibit tumor growth and reverses oxaliplatin resistance in vitro and in vivo. Conclusion: Dicer might be an acquired factor contributing to cancer malignancies in oxaliplatin-resistant CRC cells via activating the ERK pathway. The activation of the MAPK signaling pathway is Dicer-dependent in oxaliplatin-resistant CRC cells. Wnt/β-catenin inhibitors and ERK inhibitors have an anti-tumor effect in oxaliplatin-resistant cells. Citation Format: Yu-Heng Kuan, Ming-Ern Wong, Liang-Yi Hung. Dicer-dependent of ERK activation promotes the acquired oxaliplatin resistance in colorectal cancer [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 420.