Based on an improvement in overall survival (OS) the multikinase inhibitor (MKI) sorafenib is currently approved for front-line therapy of unresectable hepatocellular carcinoma (HCC). Brivanib another MKI failed to improve OS compared to sorafenib (Johnson et al, 2013). In order to identify factors which discriminate sorafenib from other MKIs beyond their different kinase profiles, we initiated an exploratory study to compare the effects of sorafenib with brivanib on the liver of healthy rats in vivo. Since the liver exhibits substantial metabolic and regenerative abilities, measureable molecular effects of MKIs were thought to become apparent using transcript profiling. Six male Wistar rats each were treated once daily with either sorafenib or brivanib at doses corresponding to respective clinically relevant doses, or corresponding vehicles. Liver samples were collected three hours after two and 15 treatments for transcript profiling on Rat ClariomD microarrays. Data were analyzed and statistically evaluated using Genedata ProfilerTM software. Genes with a minimum 1.5-fold change vs control were considered relevant. In addition, drug pharmacokinetics was analyzed from plasma after nine treatments. Clinical pathology data indicated minor effects on liver function for both compounds, consistent with previous observations for sorafenib. Mild histological changes in liver, pancreas and spleen were observed for brivanib. Sorafenib exposure was approximately 5-times lower than expected from former rat studies. Changes in gene expression were detectable in livers from treated vs. control animals supporting our hypothesis. The number of deregulated genes and the extent of deregulation were less pronounced for sorafenib probably attributed to its lower exposure. Transcript profile changes by both compounds were measurable early after two treatments and became stronger after 15 treatments. Both drugs induced changes in the expression of genes involved in vascular functions, consistent with their inhibition of VEGFR kinase, interferon / interleukin signaling, and of genes affecting metabolic pathways. Sorafenib, despite its lower exposure, selectively altered expression of genes involved in cell cycle progression and genes potentially promoting differentiation, such as vestigial-like family member 4. Vgll4 has been described as tumor suppressor by negatively regulating the formation of the YAP-TEAD transcriptional complex. In summary, the use of transcript profiling of liver tissue from healthy rats enabled us to identify genes whose expression is differentially regulated by sorafenib and brivanib and which have reasonable functional relevance. Further studies including more sophisticated models will be performed to confirm and expand these results.
Citation Format: Heidrun Ellinger-Ziegelbauer, Lukas Fiebig, Ludwig Schladt, Karl Ziegelbauer, Anette Sommer, Dieter Zopf. Differentiation of multi-kinase inhibitors by in vivo transcript profiling: Potential implications for HCC therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3935.