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Integrated multi-omics data analysis identifying novel drug sensitivity-associated molecular targets of
1Department of Medical Biology, Faculty of Medicine, Karadeniz Technical University, Trabzon 61080, Turkey.
Abstract:
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third-leading cause of malignancy-associated mortality worldwide. HCC cells are highly resistant to chemotherapeutic agents. Therefore, there are currently only two US Food and Drug Administration-approved drugs available for the treatment of HCC. The objective of the present study was to analyze the results of previously published high-throughput drug screening, and in vitro genomic and transcriptomic data from HCC cell lines, and to integrate the obtained results to define the underlying molecular mechanisms of drug sensitivity and resistance in HCC cells. The results of treatment with 225 different small molecules on 14 different HCC cell lines were retrieved from the Genomics of Drug Sensitivity in Cancer database and analyzed. Cluster analysis using the treatment results determined that HCC cell lines consist of two groups, according to their drug response profiles. Continued analyses of these two groups with Gene Set Enrichment Analysis method revealed 6 treatment-sensitive molecular targets (epidermal growth factor receptor, mechanistic target of rapamycin, deoxyribonucleic acid-dependent protein kinase, the Aurora kinases, Bruton's tyrosine kinase and phosphoinositide 3-kinase; all P<0.05) and partially effective drugs. Genetic and genome-wide gene expression data analyses of the determined targets and their known biological partners revealed 2 somatically mutated and 13 differentially expressed genes, which differed between drug-resistant and drug-sensitive HCC cells. Integration of the obtained data into a short molecular pathway revealed a drug treatment-sensitive signaling axis in HCC cells. In conclusion, the results of the present study provide novel drug sensitivity-associated molecular targets for the development of novel personalized and targeted molecular therapies against HCC.
Insights
This study identifies key molecular targets driving drug resistance in hepatocellular carcinoma (HCC). Understanding these targets, like EGFR and mTOR, can lead to new personalized therapies for liver cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacogenomics
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality with limited treatment options due to drug resistance.
- Existing therapies for HCC are insufficient, highlighting the need for novel treatment strategies.
- Understanding the molecular basis of drug sensitivity and resistance is crucial for developing effective HCC treatments.
Purpose of the Study:
- To analyze high-throughput drug screening and genomic data from HCC cell lines.
- To identify molecular mechanisms underlying drug sensitivity and resistance in HCC.
- To discover novel molecular targets for personalized HCC therapy.
Main Methods:
- Retrieved and analyzed treatment results of 225 small molecules on 14 HCC cell lines from the Genomics of Drug Sensitivity in Cancer database.
- Utilized cluster analysis to group HCC cell lines based on drug response profiles.
- Employed Gene Set Enrichment Analysis and analysis of genomic/transcriptomic data to identify molecular targets and differentially expressed genes.
Main Results:
- HCC cell lines were classified into two distinct groups based on drug response.
- Identified six key molecular targets (EGFR, mTOR, DNA-PK, Aurora kinases, BTK, PI3K) associated with drug sensitivity (P<0.05).
- Discovered 2 somatically mutated and 13 differentially expressed genes distinguishing drug-resistant from drug-sensitive HCC cells.
Conclusions:
- The study identified a novel drug-sensitive signaling axis in HCC cells.
- Novel molecular targets associated with drug sensitivity in HCC were discovered.
- These findings support the development of personalized, targeted molecular therapies for HCC.
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