Title:Epithelial-to-Mesenchymal Transition: A Mediator of Sorafenib Resistance in Advanced Hepatocellular Carcinoma
Volume: 17
Issue: 8
Author(s): Nabiel Mir, Aparna Jayachandran, Bijay Dhungel, Ritu Shrestha and Jason C. Steel*
Affiliation:
- The University of Queensland, School of Medicine, Gallipoli Medical Research Institute, Lower Lobby Level, Administration Building, Greenslopes Private Hospital, Greenslopes, Qld 4120,Australia
Keywords:
HCC, sorafenib, EMT, drug resistance, cancer stem cells, cancer.
Abstract: Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide and its incidence
is steadily rising. Currently, sorafenib remains the only approved standard treatment for patients
with advanced HCC, as it has proven to increase survival in these patients. However, clinical
and preclinical observations indicate that sorafenib treatment may have limited efficacy due to tumor
progression from the rapid development of acquired resistance. Elucidation of the underlying mechanisms
of evasive resistance to sorafenib is a major challenge in HCC research. In recent years, the
role of epithelial-to-mesenchymal transition (EMT) in the advancement of HCC and development of
drug resistance has gained increasing attention. EMT is a developmental multistep molecular and
cellular reprogramming process that is hijacked by cancer cells to enable aggressiveness. In this
review, we provide an overview of the currently available preclinical studies on the EMT
mechanisms underlying resistance to sorafenib treatment. Recent studies report enrichment of cancer
stem cells (CSCs) after sorafenib treatment. Interestingly, EMT process has been implicated in the
generation of CSCs associated with therapy resistance. We discuss how combination of sorafenib
with EMT inhibitors could enhance the clinical response to sorafenib, resulting in longer duration of
responses, than observed with sorafenib monotherapy. In particular, we discuss how these new insights
may facilitate rational development of combination therapies in the future to impact survival
of patients with advanced HCC.
