Transcriptomics-Based Drug Repurposing Approach Identifies Novel Drugs against Sorafenib-Resistant Hepatocellular Carcinoma.

Kelly Regan-Fendt,Samson T Jacob,Tasneem Motiwala,Ding Li,Peng Hu,Ryan Reyes,Lianbo Yu,Kalpana Ghoshal,Nissar A Wani,Philip R.O Payne

doi:10.3390/cancers12102730

Abstract

Simple SummaryHepatocellular carcinoma (HCC), a type of liver cancer, remains a treatment challenge due to late detection and resistance to currently approved drugs. It takes 15–20 years for a single new drug to become FDA approved. The purpose of this study was to expedite identification of novel drugs against drug-resistant HCC. For this, we matched gene expression alterations in resistant HCC with gene expression changes caused by treatment of cancer cells with drugs already FDA approved for other diseases to find the drug that can reverse the resistance-related changes. Among the identified drugs, we validated the growth inhibitory effect of two drugs, identified their mechanism in HCC and, thus, provided proof of concept evidence for validity of this drug repurposing approach with potential for use in personalized medicine.Objective: Hepatocellular carcinoma (HCC) is frequently diagnosed in patients with late-stage disease who are ineligible for curative surgical therapies. The majority of patients become resistant to sorafenib, the only approved first-line therapy for advanced cancer, underscoring the need for newer, more effective drugs. The purpose of this study is to expedite identification of novel drugs against sorafenib resistant (SR)-HCC. Methods: We employed a transcriptomics-based drug repurposing method termed connectivity mapping using gene signatures from in vitro-derived SR Huh7 HCC cells. For proof of concept validation, we focused on drugs that were FDA-approved or under clinical investigation and prioritized two anti-neoplastic agents (dasatinib and fostamatinib) with targets associated with HCC. We also prospectively validated predicted gene expression changes in drug-treated SR Huh7 cells as well as identified and validated the targets of Fostamatinib in HCC. Results: Dasatinib specifically reduced the viability of SR-HCC cells that correlated with up-regulated activity of SRC family kinases, its targets, in our SR-HCC model. However, fostamatinib was able to inhibit both parental and SR HCC cells in vitro and in xenograft models. Ingenuity pathway analysis of fostamatinib gene expression signature from LINCS predicted JAK/STAT, PI3K/AKT, ERK/MAPK pathways as potential targets of fostamatinib that were validated by Western blot analysis. Fostamatinib treatment reversed the expression of genes that were deregulated in SR HCC. Conclusion: We provide proof of concept evidence for the validity of this drug repurposing approach for SR-HCC with implications for personalized medicine.

Highlights

Liver cancer ranks seventh among the most common cancers in the world and, according to a recent report [1], it is the fourth leading cause of cancer-related death
While a small proportion of hepatocellular carcinoma (HCC) patients diagnosed at an early stage can be treated by tumor resection, cryoablation or liver transplant, these treatments are not effective in the majority of HCC patients diagnosed at an advanced stage of the disease
We address how different publicly available gene expression datasets derived from in in vitro and in vivo models of sorafenib resistance in HCC may be reliably assessed in HCC patient tissue vitro and in vivo models of sorafenib resistance in HCC may be reliably assessed in HCC patient tissue in www.mdpi.com/journal/cancers in terms of their prognostic significance and ability to derive drug repurposing predictions

Summary

Introduction

Liver cancer ranks seventh among the most common cancers in the world and, according to a recent report [1], it is the fourth leading cause of cancer-related death. The median overall survival of sorafenib treated patients is only extended by 2.8 months compared to untreated patients [3] This minimal therapeutic response is attributed to HCC tumors having an intrinsic resistance to the cytostatic effects of sorafenib [4]. In recent clinical trials in the first-line setting, nivolumab [8] or pembrolizumab [9] could not significantly improve survival of HCC patients compared to sorafenib and best supportive care, respectively. Lenvatinib, another multi-kinase inhibitor, recently approved as first-line therapy for advanced HCCs, was not significantly superior to sorafenib in improving overall survival in clinical trials [10]. There is an urgent need to develop therapeutic strategies to overcome sorafenib resistance and discover new, more effective therapies

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