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

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of cancer-related deaths worldwide [1,2]. Chronic liver inflammation resulting from prolonged viral hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis and other metabolic disorders such as excessive alcohol consumption and exposure to aflatoxins represent major etiological factors for HCC [1-3]. These multitude of underlying mechanisms that affect disease course and patient prognosis underscores the importance of a broad-spectrum approach to target multiple mechanisms underlying HCC development and promotion [4]. Current therapies for HCC include specific tyrosine kinase inhibitors (TKIs) such as sorafenib (Nexavar®), regorafenib (Stivarga®), lenvatinib (Lenvima®) and cabozantinib (Cabometyx®) [5-9]. In addition, immunotherapies with nivolumab (Opdivo®) and pembrolizumab (Keytruda®) both inhibiting programmed cell death receptor PD-1, have also been approved as second line treatment for advanced HCC [10,11]. Although these therapies have shown significant clinical benefits for HCC patients, but the clinical response rate is still low. Thus, there is an immediate need for drugs, preferentially with different mechanisms, which could be used in suitable combinations to complement existing therapies and to improve clinical outcome without compromising safety.