In-Silico Evaluation of Genetic Alterations in Ovarian Carcinoma and Therapeutic Efficacy of NSC777201, as a Novel Multi-Target Agent for TTK, NEK2, and CDK1.

Yu-Chi Wang,Ntlotlang Mokgautsi,Bashir Lawal,Maryam Rachmawati Sumitra,Harshita Nivrutti Khedkar,Prateeti Srivastava,Hsu-Shan Huang,Vijesh Kumar Yadav,Alexander T H Wu

doi:10.3390/ijms22115895

Abstract

Ovarian cancer is often detected at the advanced stages at the time of initial diagnosis. Early-stage diagnosis is difficult due to its asymptomatic nature, where less than 30% of 5-year survival has been noticed. The underlying molecular events associated with the disease’s pathogenesis have yet to be fully elucidated. Thus, the identification of prognostic biomarkers as well as developing novel therapeutic agents for targeting these markers become relevant. Herein, we identified 264 differentially expressed genes (DEGs) common in four ovarian cancer datasets (GSE14407, GSE18520, GSE26712, GSE54388), respectively. We constructed a protein-protein interaction (PPI) interaction network with the overexpressed genes (72 genes) and performed gene enrichment analysis. In the PPI networks, three proteins; TTK Protein Kinase (TTK), NIMA Related Kinase 2 (NEK2), and cyclin-dependent kinase (CDK1) with higher node degrees were further evaluated as therapeutic targets for our novel multi-target small molecule NSC777201. We found that the upregulated DEGs were enriched in KEGG and gene ontologies associated with ovarian cancer progression, female gamete association, otic vesicle development, regulation of chromosome segregation, and therapeutic failure. In addition to the PPI network, ingenuity pathway analysis also implicate TTK, NEK2, and CDK1 in the elevated salvage pyrimidine and pyridoxal pathways in ovarian cancer. The TTK, NEK2, and CDK1 are over-expressed, demonstrating a high frequency of genetic alterations, and are associated with poor prognosis of ovarian cancer cohorts. Interestingly, NSC777201 demonstrated anti-proliferative and cytotoxic activities (GI50 = 1.6 µM~1.82 µM and TGI50 = 3.5 µM~3.63 µM) against the NCI panels of ovarian cancer cell lines and exhibited a robust interaction with stronger affinities for TTK, NEK2, and CDK1, than do the standard drug, paclitaxel. NSC777201 displayed desirable properties of a drug-like candidate and thus could be considered as a novel small molecule for treating ovarian carcinoma.

Highlights

Ovarian cancer ranks as the sixth most common cancer and most lethal of all gynecologic malignancies worldwide [1]
A total of 264 common differentially expressed genes (DEGs) were observed in ovarian carcinoma as compared to the normal adjacent tissues (Figure 1B) (Supplementary Material File S1)
We used the gene expression profiling interactive analysis (GEPIA) web-based tool [59] to investigate the roles of these genes in ovarian cancer; interestingly, we found that expressions of TTK, NIMA Related Kinase 2 (NEK2), and CDK1 were correlated with tumor stages. mRNA levels of TTK, NEK2, and CDK1 increased during the development of cancer from stage 1 to stage 4 (Figure 5D)

Summary

Introduction

Ovarian cancer ranks as the sixth most common cancer and most lethal of all gynecologic malignancies worldwide [1]. Within 2 years, most patients undergo disease recurrence and relapsed ovarian cancer lacks successful care choices. Ovarian cancer mortality rates rank first among gynecological malignant tumors [2]. Long-term survival in ovarian cancer remains poor as a consequence of drug resistance, which results in fatal disease [3]. Genes, whose activation leads to cancer development known as oncogenes, account for drug resistance in cancer [5]. In chondrosarcomas, the leukemia/lymphoma-related factor, the LRF gene is an oncogene related to the survival factor and contributes to drug resistance and tumor malignancy [6]

Methods

Results

Conclusion