Hepatocellular carcinoma (HCC) is often diagnosed in patients with advanced disease who are ineligible for curative surgical therapies. Sorafenib is the only approved drug for treating late stage HCC patients. However, patients rapidly become unresponsive due to inherent and acquired drug resistance. The promise of drug repurposing is that identifying new uses for existing drugs may reduce the high costs and time required for drug discovery. This is the first study employing connectivity mapping, a transcriptomics-based drug repurposing method, to identify drugs for use against sorafenib resistant (SR)-HCC via reversal of gene expression patterns. As a first step, we characterized gene expression signatures of different models of sorafenib resistance. We obtained gene expression signatures from an in vitro and an in vivo model of (SR)-HCC (publicly available microarray data) as well as from sorafenib-resistant (pool and clone) Huh7 cells generated in our lab. We determined the presence of the SR-HCC gene signatures across six patient-derived HCC gene expression datasets from the Gene Expression Omnibus (GEO) database using the nearest template method (FDR<0.05), and found that the gene signatures performed similarly in distinguishing tumor vs. normal liver tissue (FET p<0.05). We also analyzed RNAseq data from HCC patients (n=423) in The Cancer Genome Atlas (TCGA) for the presence of these SR gene signatures, and observed that patients harboring the SR-HCC gene signatures generated by our lab had significantly reduced survival (log-rank p=0.036 SR Huh7 pool; p=0.009 SR Huh7 clone). Utilizing drug-induced gene expression profiles (n= 3,740 drugs) in the HepG2 HCC cell line from the Library of Integrated Network-based Cellular Signatures (LINCS) database, we applied connectivity mapping analysis to the SR-HCC gene signatures. Dasatinib, a Src family kinase inhibitor, was prioritized as a top drug candidate from our LINCS analysis to reverse HCC sorafenib resistance. We confirmed up-regulated activity of Src family kinases in SR-Huh7 cells, as compared to sorafenib sensitive Huh7 cells (two-tailed t test, p<0.05). We validated the use of dasatinib against sorafenib-resistant HCC cells in vitro alone and in combination with sorafenib using cell viability and clonogenic survival assays. In summary, we provide physiological relevance of SR models and proof of concept evidence for the validity of this novel drug repurposing approach for SR-HCC with implications for personalized medicine.
Citation Format: Kelly Regan, Ryan Reyes, Samson Jacob, Philip Payne, Tasneem Motiwala. Drug repurposing for hepatocellular carcinoma enabled via transcriptomics data from experimental models of sorafenib resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1562. doi:10.1158/1538-7445.AM2017-1562