Hepatocellular Carcinoma: Molecular Mechanisms and Targeted Therapies

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors worldwide. HCC is a complex process that is associated with several etiological factors, which in turn result in aberrant activation of different cellular and molecular pathways and the disruption of balance between activation and inactivation of protooncogenes and tumor suppressor genes, respectively. Since HCC most often occurs in the setting of a diseased or cirrhotic liver and most of the patients are diagnosed at the late stage of disease, prognosis is generally poor. At present, limited treatment options with marginal clinical benefits are available. Systemic therapy, particularly in the form of conventional cytotoxic drugs, are generally ineffective. In recent years, molecular-targeted therapies have been clinically used to treat various cancers, including liver cancer. This approach inhibits the growth of tumor cells by interfering with molecules that are involved in carcinogenesis, which makes it more selective and specific than cytotoxic chemotherapy. Many clinical trials have been carried out while using molecular targeted drugs in advanced HCC with many more in progress. The clinical trials in HCC to date have evaluated a single-targeted therapy alone, or two or more targeted therapies in parallel. The aim of this review is to provide insight of various molecular mechanisms, leading to HCC development and progression, and also the range of experimental therapeutics for patients with advanced HCC. The review will summarize different clinical trials data the successes and failures of these treatments, as well as the most effective and approved drugs designed against HCC.

JAK/STAT signaling in hepatocellular carcinoma

“…Aberrant activation of various intracellular signaling pathways involved in cell growth, differentiation, apoptosis and survival have been found to contribute to HCC development and progression [22,23]. These include known oncogenic signaling pathways such as Wnt/β-catenin pathway, PI3K/Akt/mTOR pathway, Ras/Raf/MAPK pathway and JAK/STAT pathway [23].…”

Stabilization of Hypoxia-Inducible Factors and BNIP3 Promoter Methylation Contribute to Acquired Sorafenib Resistance in Human Hepatocarcinoma Cells

“…Hepatocarcinoma (HCC), a common malignancy worldwide with a quick rise in incidence, is one of the main causes of cancer-related death because of its high mortality rate [1]. Most of HCC cases are diagnosed in advanced stages, when there are no healing therapies available and the first-line therapy employed is the palliative treatment with sorafenib (BAY 43-9006, Nexavar ® ), an oral multikinase inhibitor with antiproliferative, proapoptotic, and antiangiogenic properties [2].…”

“…The antiproliferative activity responds to the suppression of the serine/threonine kinases Raf-1 and B-Raf, with the consequent inhibition of the mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK) signaling pathway. The proapoptotic action of the drug is associated with the inhibition of eIF4E phosphorylation and subsequent downregulation of the antiapoptotic factor induced myeloid leukemia cell differentiation protein (Mcl-1) translation [1,3]. Furthermore, sorafenib exerts its antiangiogenic activity by targeting the tyrosine kinase receptors mast/stem cell growth factor receptor (c-Kit), FMS-like tyrosine kinase (FLT-3), vascular endothelial growth factor receptors 2 and 3 (VEGFR-2, VEGFR-3), and platelet-derived growth factor receptor (PDGFR-β) [3].…”

“…The results obtained from the sorafenib hepatocellular carcinoma assessment randomized protocol (SHARP) clinical trial showed that this drug is effective and safe, encouraging the approval of sorafenib for advanced HCC [1]. Nonetheless, the efficacy of sorafenib is quite brief, since it extends the patients survival only in a few months due to the appearance of resistant HCC cells [2].…”

Long non‑coding RNA BCAR4 promotes liver cancer progression by regulating proliferation, migration and invasion

“…Curative therapies such as resection or transplantation are not suitable for patients with advanced stage LC, and advanced LCs are resistant to the majority of standard chemotherapeutic regimens (3). Therefore, the overall survival (OS) of patients with LC is dismal, with a five-year survival rate of <15% in USA (3)(4)(5). Therefore, current research efforts are directed towards the discovery of biomarkers for early diagnosis, recognition of molecular subclasses of LC, correlation of molecular signatures with radiological/histological features, characterization of new therapeutic targets and personalization of therapies based on an individual's tumor biology (6).…”