Repurposing of PI3K inhibitors for high-grade serous ovarian cancer: A novel competing endogenous network analysis-based approach

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INTRODUCTION: The average survival time for High-Grade Serous Ovarian Cancer (HGSOC) is around 3.4 years post-diagnosis. The treatment options are limited, especially for relapsed patients, resistant to standard treatment. Therefore, novel drug candidates are needed. OBJECTIVE: We propose a novel approach for predicting potential drug candidates by focusing on agents capable of reversing the effects of perturbed RNA network. METHODS: The competing endogenous RNA (ceRNAs) network was constructed on differential expression (DE) of long non-coding RNAs (lncRNAs), protein-coding RNAs (mRNAs) and microRNAs (miRNAs) from the primary HGSOC tumour tissues. It allowed for identification of key perturbed axes of RNA regulation. The publicly available resources for drug repurposing were used to select candidates for in-vitro validation. RESULTS: The phosphoinositide 3-kinase (PI3K) pathway, known to be involved in developing drug resistance in ovarian cancer, was identified as highly dependent from the coding and non-coding RNA interactions. PI3K pathway inhibitors, PI-103 and ZSTK474, were identified as drug candidates and their efficacy against HGSOC was confirmed in vitro. E2F1 and SNAI2 are essential transcription factors (TFs) known for regulating critical cancer pathways such as cell cycle repair or epithelial-mesenchymal transition (EMT). In our study, these TFs were identified as hub regulators within the ceRNA network. CONCLUSION: Investigation of fine-tune regulation of RNA by non-coding RNAs and TFs uncovered a significant role of ceRNA network in cancer development, highlighting its integration with master regulatory pathways that drive tumor progression and sustainability. The drug repurposing workflow based on ceRNA-limited differentially expressed mRNAs allowed for effective prioritization of compounds with potential to be applied as treatment.

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