PO-012 Pre-clinical Insight into How Platelet Count Affects the Activity of HDACi Resminostat in Combination with the Multi-Kinase Inhibitor Sorafenib in HCC

Introduction In a recent phase I/II clinical trial in hepatocellular carcinoma (HCC), (NCT02400788), the combination of HDAC-inhibitor resminostat (YHI1001) with a multi-kinase inhibitor sorafenib was clinically beneficial compared to sorafenib mono-treatment in patients with platelet counts ≥1.5 × 105/µl, but not below that threshold. In HCC, platelets have been linked to bad prognosis, tumour growth and metastasis as well as to resistance against the standard treatment with sorafenib. This begs the question how platelets affect HCC cells and modulate their drug response. Material and methods Several HCC cell lines were used to compare phenotypical features, susceptibility to platelets and drug-mediated effects. To determine effects on cancer cell features, in vitro cell growth and transwell invasion assays were performed. Furthermore, the underlying mechanism of a platelet-modulated drug response on the molecular level was explored. Results and discussions In HCC cells, the anti-proliferative potency of sorafenib was counteracted by platelet factors and the mesenchymal phenotype. However, resminostat alone and in combination with sorafenib effectively triggered an anti-proliferative response independently of platelets or the mesenchymal phenotype. Therefore, resminostat determined the anti-proliferative response of the drug combination. Moreover, recent reports highlight HCC cell subpopulations which express cancer stem cell genes and harbour clonogenic growth and cell invasive capacities as critical for metastasis. Intriguingly, we found that platelets induced the cell-invasive capacity in HCC cells with detectable levels of several cancer stem cell markers and which featured a mixed epithelial-mesenchymal phenotype. Importantly, only the combination of resminostat with sorafenib, but not the mono-treatments, significantly reversed the platelet-induced cell invasion. Conclusion Our pre-clinical data provide evidence on how platelets mediate pro-tumorigenic effects and modulate the therapeutic response to the resminostat/sorafenib drug combination. Platelet factors negatively modulated the drug response to sorafenib. This was overcome by the anti-proliferative activities of resminostat. Importantly, providing an explanation for the clinical benefit of the combination therapy, the platelet-induced invasive capacity was reversed only by the combination of resminostat with sorafenib, but not the mono-treatments.