Akademik Veri Yönetim Sistemi
EACR 2022 Annual Meeting, Sevilla, İspanya, 20 - 23 Haziran 2022, ss.3-4
Introduction
Hepatocellular carcinoma (HCC) is one of the most common and deadliest cancer
worldwide. It is highly resistant to conventional chemotherapies due to the hyperactivation of
many critical survival signaling pathways, and targeted agents can extend the patient’s
survival for a few months. Furthermore, HCC patients have limited chemotherapeutics due to
impaired liver functions. Thus, it is crucial to identify drugs and drug combinations for
repurposing in HCC treatment.
Material and Methods
The pathways involved in hepatocarcinogenesis were used for the generation of a directed
network, in which small molecule inhibitor drugs having at least one target protein were also
integrated. The target proteins and their interactions were calculated; the functionality of the
network was identified. Top nine ranked drugs were selected to validate their bioactivities on
HCC cell lines in vitro by NCI-SRB assay. Transcriptomic analysis was done by Nanostring
nCounter system using the PanCancer Pathways panel. Synergistic drug combinations were
determined by analyzing NCI-SRB results using SynergyFinder. The molecular mechanisms
induced by single drugs and drug combinations were studied by cell cycle assay, cell death
assay, and western blotting.
Results and Discussions
Amrinone, Thalidomide, Chloroquine, Sunitinib, Pranlukast, Pseudoephedrine, Brigatinib,
Lenvatinib, and Regorafenib were ranked as the first nine potent drugs. Except for
Thalidomide, Pranlukast, Amrinone, Pseudoephedrine, the selected drugs, especially
Brigatinib and Sunitinib, were remarkably bioactive on the HCC cells. Several cancer-related
genes and pathways were altered in the presence of drugs, with Brigatinib having the
highest number of differentially expressed genes (DEGs). The most enriched signaling
pathways were Wnt-beta catenin, cell cycle, and MAPK. Brigatinib differed from the rest of
the drugs in the pathway scoring matrix. Apart from the previously reported genes, HDAC1,
HDAC2, HDAC4, FOS, DAXX, LEF1, RELA, and RUNX, etc., that were not associated with
liver cancer therapeutics before were significantly enriched in the network. The bioactive
drugs induced apoptosis involving Akt pathway inactivation due to cell cycle arrest in G0/G1
phase. Furthermore, combinations of Brigatinib with Amrinone, Sunitinib or Regorafenib, and
Sunitinib with Pseudoephedrine or Chloroquine had synergistic effects on HCC cells.
Conclusion
Our results have shown that our network-based in silico model can be exploited for drug
repurposing and novel target identification.