QSAR-Based Drug Repurposing and RNA-Seq Metabolic Networks Highlight Treatment Opportunities for Hepatocellular Carcinoma Through Pyrimidine Starvation

TL;DR

This paper explores new treatment options for liver cancer by identifying drugs that can disrupt pyrimidine metabolism, a key pathway for cancer cell growth.

Contribution

The study combines drug repurposing and metabolic modeling to identify approved drugs that may inhibit HCC through pyrimidine starvation.

Findings

DHODH and TYMS are essential genes in HCC's pyrimidine metabolism pathway.

Oteseconazole, Tipranavir, and Lusutrombopag are potential inhibitors of DHODH.

Tadalafil, Dabigatran, Baloxavir Marboxil, and Candesartan Cilexetil are promising TYMS inhibitors.

Abstract

The challenges associated with the efficacy of systemic therapy options for Hepatocellular Carcinoma (HCC) are contributing to the high mortality rate of the disease in advanced cases. There is an urgent need to develop new drugs and treatment regimens that are effective regardless of HCC’s molecular heterogeneity. However, the costly and uncertain nature of drug development often deters risk-averse investors. To address this, the study employs a combination of drug repositioning and metabolic vulnerability searching to identify approved drugs with high potential to inhibit an essential metabolic pathway. Overall, this research highlights the metabolic vulnerabilities of HCC and proposes the testing of the suggested approved drugs as potential anti-HCC therapies.

Background/Objectives: The molecular heterogeneity and metabolic flexibility of Hepatocellular Carcinoma (HCC) pose significant challenges to the efficacy of systemic therapy for advanced cases. Early screening difficulties often delay diagnosis, leading to more advanced stages at presentation. Combined with the inconsistent responses to current systemic therapies, HCC continues to have one of the highest mortality rates among cancers. Thus, this paper seeks to contribute to the development of systemic therapy options through the consideration of HCC’s metabolic vulnerabilities and lay the groundwork for future in vitro studies. Methods: Transcriptomic data were used to calculate single and double knockout options for HCC using genetic Minimal Cut Sets. Furthermore, using QSAR modeling, drug repositioning opportunities were assessed to inhibit the selected genes. Results: Two single knockout options that were also annotated as essential pairs were found within the pyrimidine metabolism pathway of HCC, wherein the knockout of either DHODH or TYMS is potentially disruptive to proliferation. The result of the flux balance analysis and gene knockout simulation indicated a significant decrease in biomass production. Three machine learning algorithms were assessed for their performance in predicting the pIC50 of a given compound for the selected genes. SVM-rbf performed the best on unseen data achieving an R2 of 0.82 for DHODH and 0.81 for TYMS. For DHODH, the drugs Oteseconazole, Tipranavir, and Lusutrombopag were identified as potential inhibitors. For TYMS, the drugs Tadalafil, Dabigatran, Baloxavir Marboxil, and Candesartan Cilexetil showed promise as inhibitors. Conclusions: Overall, this study suggests in vitro testing of the identified drugs to assess their capabilities in inducing pyrimidine starvation on HCC.

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