Is the era of sorafenib over? A review of the literature

Abstract

Hepatocellular carcinoma (HCC) is one of the most severe diseases worldwide. For the different stages of HCC, there are different clinical treatment strategies, such as surgical therapy for the early stage, and transarterial chemoembolization (TACE) and selective internal radiation therapy (SIRT) for intermediate-stage disease. Systemic treatment, which uses mainly targeted drugs, is the standard therapy against advanced HCC. Sorafenib is an important first-line therapy for advanced HCC. As a classically effective drug, sorafenib can increase overall survival markedly. However, it still has room for improvement because of the heterogeneity of HCC and acquired resistance. Scientists have reported the acquired sorafenib resistance is associated with the anomalous expression of certain genes, most of which are also related with HCC onset and development. Combining sorafenib with inhibitors targeting these genes may be an effective treatment. Combined treatment may not only overcome drug resistance, but also inhibit the expression of carcinoma-related genes. This review focuses on the current status of sorafenib in advanced HCC, summarizes the inhibitors that can combine with sorafenib in the treatment against HCC, and provides the rationale for clinical trials of sorafenib in combination with other inhibitors in HCC. The era of sorafenib in the treatment of HCC is far from over, as long as we find better methods of medication.

Keywords: combination; hepatocellular carcinoma; inhibitor; resistance; sorafenib.

Figure 1.

Factors preventing more patients benefitting from sorafenib. To date, about six factors have been identified to interfere with the effect of sorafenib. Economic burden, acquired resistance, genetic heterogeneity, and adverse reaction are widely accepted factors. The liver is the main metabolic site of sorafenib; therefore, the status of the liver can also influence the effect of sorafenib. Sorafenib cannot kill cancer stem cells effectively; therefore, the existence of cancer stemness is another important factor. HCC, hepatocellular carcinoma.

Figure 2.

Theoretical research and clinical application of PI3K/AKT/mTOR inhibitors and sorafenib. The PI3K/AKT/mTOR signal pathway plays a key role in the occurrence and development of HCC, and resistance to sorafenib. Combinations of PI3K/AKT/mTOR inhibitors and sorafenib showed satisfactory results in the treatment of HCC. The two inhibitors above plus 3-MA (an autophagy inhibitor) demonstrated a better treatment effect. As a type of immune inhibitor, mTOR inhibitors combined with sorafenib may also prevent post-transplant HCC. AKT, phosphatidylinositol 3-kinase (PI3K)/protein kinase B; ATO, arsenic trioxide; HCC, hepatocellular carcinoma; IL-6, interleukin-6; INK128, Sapanisertib; 3-MA, 3-methyladenine; mTOR, mammalian target of rapamycin; ROS, reactive oxygen species; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor.

Figure 3.

Roles and solutions of autophagy in HCC development and sorafenib resistance. The role of autophagy in HCC development and sorafenib resistance remains controversial. Most studies showed that inhibiting autophagy could enhance the effect of sorafenib through multiple pathways. A few research studies have reported that autophagy can induce cell apoptosis and plays a synergistic role with sorafenib. HCC, hepatocellular carcinoma; 3-MA, 3-methyladenine; mAb, monoclonal antibody.

Figure 4.

Mechanisms of sorafenib resistance and HCC development, and combination therapies to treat HCC. Current research about the combinations of sorafenib and other inhibitors demonstrates the feasibility of drug combination. Through mechanistic research and clinical trials, scientists can find more treatments against HCC.