Abstract 2645: Targeting mRNA processing pathways in ovarian cancer with a small molecule inhibitor

Abstract

Abstract mRNA processing related pathways, including spliceosome and ribosome are over-expressed and unregulated in cancer cells. To investigate the mRNA processing pathways in patient samples, we performed a comprehensive, tandem mass tag (TMT) labeling-based proteome and phosphoproteome profiling of the normal and ovarian cancerous tissues from patients treated with different chemotherapy revealed that malignant cells have overexpression of mRNA processing pathways compared to normal cells. For this analysis, equal amount of tissues were homogenized, and tissue lysates were collected and processed for the quantitative proteomics and phosphoproteomics analysis. KEGG pathway enrichment analysis revealed that spliceosome, basal transcription factors, mRNA surveillance, ribosome and ribosome biogenesis in eukaryotes pathways are upregulated in cancer cells compared to control. On other hand, pathways associated with metabolism and fatty acid biosynthesis were downregulated in malignant cells. Moreover, kinase Enrichment Analysis shows that CDK2, ATM, ATR, and MAPK associated kinases are upregulated in cancer cells compared to normal. Based on proteome analysis of patient samples, we investigated the pharmacological inhibition of Y-box binding protein 1 (YB-1). This is an RNA binding protein and key regulator of pre-mRNA alternative splicing and processing. We recently showed that a natural product-derived small molecule (SU056) inhibits YB-1 activity. We found that SU056 binds to the YB-1 and blocks the RNA binding pocket. Proteomics results suggest that treatment with this drug strongly inhibits the spliceosome pathway. SU056 treatment arrests the ovarian cancer cells in G1 phase and inhibits the CDK2 and Cyclin E. SU056 inhibits the tumor progression and metastasis in the ID8 mice model and sensitizes the OVCAR8 NSG mice model for paclitaxel treatment. Our study provides a compelling case for YB-1 inhibition using SU056 as a potential therapy for ovarian cancer. Citation Format: Dhanir Tailor, Chia-Feng Tsai, Alexander Honkala, Wenqi Li, Tao Liu, Tanja Pejovic, Sanjay V. Malhotra. Targeting mRNA processing pathways in ovarian cancer with a small molecule inhibitor [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 2645.