Milciclib and sorafenib synergistically downregulate c-Myc to suppress tumor growth in an orthotopic murine model of human hepatocellular carcinoma

Complex heterogeneity in HCC pateints, due to multiple etiological factors, implies that monotherapy targeting a single mechanism might not be sufficient for sustained clinical response as another compensatory signaling could get activated to develop drug resistance. Thus, combination therapies utilizing drugs, preferentially with different mode of action, might be clinically more satisfactory. Milciclib (PHA-848125AC), a pan-inhibitor of cyclin dependent kinases (CDKs: CDK1, CDK2, CDK4, CDK5 and CDK7) and c-Src kinase, has shown anti-cancer activity in tumor models as well as in clinical studies with cancer patients, including HCC. Here, we present data demonstrating anti-HCC activity of milciclib in cell lines as well as in two different animal models HCC. Importantly, milciclib exhibited synergistic anti-HCC effect with sorafenib, a first-line tyrosine kinase inhibitor (TKI) drug for HCC. Oral treatment with milciclib inhibited HCC tumor growth in TG221 mice, a miR-221-induced transgenic HCC model. We also developed an orthotopic model, by implanting human HCC cells (MHCC97-H) in liver of nude mice, in which tumor growth can be monitored by measuring serum levels of human -fetoprotein (hAFP) but not mouse AFP. While milciclib or sorafenib alone inhibited tumor growth, the combination of these two drugs produced remarkable synergistic anti-HCC activity. Mechanism related tumor tissue analyses indicated that while milciclib and sorafenib inhibited their respective signaling pathways, these drugs interacted with each other to downregulate c-Myc to exert their synergistic anti-HCC activity. Our results suggest that milciclib may complement with a TKI to improve clinical outcome in advanced HCC patients.