Hepatocellular carcinoma and sorafenib: too many resistance mechanisms?

Hepatocellular carcinoma (HCC), the most common tumour of the liver, develops in more than 80% of cases on patients with chronically damaged livers owing to excessive alcohol consumption, hepatitis B or C virus (HBV or HCV) infection or obesity. Despite positive results of HBV vaccination programmes and the promising data from the new anti-HCV treatments,1 the incidence of HCC is increasing significantly in Western countries because of the progression of old HCV infections and the almost epidemic prevalence of obesity and metabolic syndrome-associated non-alcoholic fatty liver disease.2 The prognosis of patients with HCC is generally very poor. HCC tumours are resistant to chemotherapy and are usually diagnosed at a late stage when the curative strategies of surgical resection and orthotopic liver transplantation are not applicable. Targeted treatments against specific oncogenes have been shown to be effective in the treatment of leukaemias and solid tumours such as breast, colon and lung carcinomas.3 In 2008, the SHARP (Sorafenib HCC Assessment Randomised Protocol) trials showed an improved overall survival in Child–Pugh class A patients with advanced HCC upon treatment with the antiangiogenic and antiproliferative agent sorafenib.4 This multikinase inhibitor was established as the standard of care for patients with advanced HCC. However, the promising systemic treatment has demonstrated limited survival benefits with very low rates of tumour response, suggesting the existence of primary and acquired drug resistance mechanisms.5 In this situation HCC appears to be a moving target, and a rapid intervention in at …